Mark Johan van Raaij

Publications

• 0.55

  Impact points

  Crystallization of the C-terminal domain of the bacteriophage T7 fibre protein gp17.

  Carmela Garcia-Doval, Mark J van Raaij

  Acta crystallographica. Section F, Structural biology and crystallization communications. 02/2012; 68(Pt 2):166-71.

  Bacteriophage T7 attaches to its host using the C-terminal domains of its six fibres, which are trimers of the gp17 protein. A C-terminal fragment of gp17 consisting of amino acids 371-553 has been expressed, purified and crystallized. Crystals of two forms were obtained, belonging to space group P2... [more] Bacteriophage T7 attaches to its host using the C-terminal domains of its six fibres, which are trimers of the gp17 protein. A C-terminal fragment of gp17 consisting of amino acids 371-553 has been expressed, purified and crystallized. Crystals of two forms were obtained, belonging to space group P2(1)2(1)2(1) (unit-cell parameters a = 61.2, b = 86.0, c = 118.4 Å) and space group C222(1) (unit-cell parameters a = 68.3, b = 145.6, c = 172.1 Å). They diffracted to 1.9 and 2.0 Å resolution, respectively. Both crystals are expected to contain one trimer in the asymmetric unit. Multiwavelength anomalous dispersion phasing with a mercury derivative is in progress.
• 4.80

  Impact points

  A prodrug approach for improving antituberculosis activity of potent Mycobacterium tuberculosis type II dehydroquinase inhibitors.

  Lorena Tizón, José M Otero, Verónica F V Prazeres, Antonio L Llamas-Saiz, Gavin C Fox, Mark J van Raaij, Heather Lamb, Alastair R Hawkins, José A Ainsa, Luis Castedo, Concepción González-Bello

  Journal of medicinal chemistry. 08/2011; 54(17):6063-84.

  The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was st... [more] The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was studied. The crystal structures of Mycobacterium tuberculosis type II dehydroquinase in complex with three of the reported inhibitors are also described. The results show that an aromatic substituent on C2 prevents the closure of the active site by impeding the hydrogen-bonding interaction of Arg108 with the essential Tyr24 of the flexible loop, the residue that initiates catalysis. Chemical modifications of the reported acids were also carried out to improve internalization into Mycobacterium tuberculosis through an ester prodrug approach. Propyl esters proved to be the most efficient in achieving optimal in vitro activities.

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• 2.82

  Impact points

  Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives.

  Annemiek D Knijnenburg, Varsha V Kapoerchan, Gijsbert M Grotenbreg, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Bep Ravensbergen, Peter H Nibbering, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Bioorganic & medicinal chemistry. 06/2011; 19(11):3402-9.

  In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar si... [more] In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar side chain of the additional d-amino acid residue is positioned at the same face of the molecule as the hydrophobic side chains, and we believe that because of this compound 2 is considerably less hydrophobic than extended GS derivatives in which the strand regions are exclusively composed of l-amino acids. Using this backbone structure as our benchmark we prepared a small series of ring-extended GS analogues featuring sugar amino acid dipeptide isosteres of varied hydrophobicity at the turn region. We show that via this approach hydrophobicity of extended GS analogues can be tuned without affecting the secondary structure (as observed from NMR and CD spectra). Biological evaluation reveals that hydrophobicity correlates to cell toxicity, but still bacteriolysis is induced with GS analogues that are too hydrophilic to efficiently lyse human red blood cells.

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• 5.38

  Impact points

  Exploring the conformational and biological versatility of β-turn-modified gramicidin S by using sugar amino acid homologues that vary in ring size.

  Annemiek D Knijnenburg, Adriaan W Tuin, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Chemistry (Weinheim an der Bergstrasse, Germany). 03/2011; 17(14):3995-4004.

  Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the... [more] Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties determines the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-containing peptides is solvent dependent. The derivative containing the pyranoid SAA is slightly less hydrophobic and displays a diminished haemolytic activity, but has similar antimicrobial properties as GS.

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• 3.23

  Impact points

  Evaluation of readily accessible azoles as mimics of the aromatic ring of D-phenylalanine in the turn region of gramicidin S.

  Matthijs van der Knaap, Lianne T Lageveen, Henk J Busscher, Roos Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Gijsbert A van der Marel, Herman S Overkleeft, Mark Overhand

  ChemMedChem. 03/2011; 6(5):840-7.

  The influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidin S was investigated against a representative panel of Gram-positive and Gram-negative bacteria strains. Substituted triazole derivativ... [more] The influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidin S was investigated against a representative panel of Gram-positive and Gram-negative bacteria strains. Substituted triazole derivatives, obtained using a convergent synthetic strategy, are as active as gramicidin S, provided that any substituent on the triazole moiety is not too large. The unsubstituted triazole derivative was biologically less active than the parent natural product, gramicidin S. In general for the triazole series, the hemolytic activity could be correlated with the antibacterial activity, that is, the higher the antibacterial activity, the higher the toxicity towards blood cells. Interestingly, its imidazole counterpart showed high antibacterial activity, combined with significantly diminished hemolytic activity.

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• 3.23

  Impact points

  Tetrahydrobenzothiophene derivatives: conformationally restricted inhibitors of type II dehydroquinase.

  Sonia Paz, Lorena Tizón, José M Otero, Antonio L Llamas-Saiz, Gavin C Fox, Mark J van Raaij, Heather Lamb, Alastair R Hawkins, Adrian J Lapthorn, Luis Castedo, Concepción González-Bello

  ChemMedChem. 02/2011; 6(2):266-72.

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• 3.09

  Impact points

  Target highlights in CASP9: Experimental target structures for the critical assessment of techniques for protein structure prediction.

  Andriy Kryshtafovych, John Moult, Sergio G Bartual, J Fernando Bazan, Helen Berman, Darren E Casteel, Evangelos Christodoulou, John K Everett, Jens Hausmann, Tatjana Heidebrecht, [......], José M Otero, Anastassis Perrakis, Juan C Pizarro, Mark J van Raaij, Theresa A Ramelot, Francois Rousseau, Liang Tong, Amy K Wernimont, Jasmine Young, Torsten Schwede

  Proteins. 01/2011; 79 Suppl 10:6-20.

  One goal of the CASP community wide experiment on the critical assessment of techniques for protein structure prediction is to identify the current state of the art in protein structure prediction and modeling. A fundamental principle of CASP is blind prediction on a set of relevant protein targets,... [more] One goal of the CASP community wide experiment on the critical assessment of techniques for protein structure prediction is to identify the current state of the art in protein structure prediction and modeling. A fundamental principle of CASP is blind prediction on a set of relevant protein targets, that is, the participating computational methods are tested on a common set of experimental target proteins, for which the experimental structures are not known at the time of modeling. Therefore, the CASP experiment would not have been possible without broad support of the experimental protein structural biology community. In this article, several experimental groups discuss the structures of the proteins which they provided as prediction targets for CASP9, highlighting structural and functional peculiarities of these structures: the long tail fiber protein gp37 from bacteriophage T4, the cyclic GMP-dependent protein kinase Iβ dimerization/docking domain, the ectodomain of the JTB (jumping translocation breakpoint) transmembrane receptor, Autotaxin in complex with an inhibitor, the DNA-binding J-binding protein 1 domain essential for biosynthesis and maintenance of DNA base-J (β-D-glucosyl-hydroxymethyluracil) in Trypanosoma and Leishmania, an so far uncharacterized 73 residue domain from Ruminococcus gnavus with a fold typical for PDZ-like domains, a domain from the phycobilisome core-membrane linker phycobiliprotein ApcE from Synechocystis, the heat shock protein 90 activators PFC0360w and PFC0270w from Plasmodium falciparum, and 2-oxo-3-deoxygalactonate kinase from Klebsiella pneumoniae.
• 9.43

  Impact points

  Structure of the bacteriophage T4 long tail fiber receptor-binding tip.

  Sergio G Bartual, José M Otero, Carmela Garcia-Doval, Antonio L Llamas-Saiz, Richard Kahn, Gavin C Fox, Mark J van Raaij

  Proceedings of the National Academy of Sciences of the United States of America. 11/2010; 107(47):20287-92.

  Bacteriophages are the most numerous organisms in the biosphere. In spite of their biological significance and the spectrum of potential applications, little high-resolution structural detail is available on their receptor-binding fibers. Here we present the crystal structure of the receptor-binding... [more] Bacteriophages are the most numerous organisms in the biosphere. In spite of their biological significance and the spectrum of potential applications, little high-resolution structural detail is available on their receptor-binding fibers. Here we present the crystal structure of the receptor-binding tip of the bacteriophage T4 long tail fiber, which is highly homologous to the tip of the bacteriophage lambda side tail fibers. This structure reveals an unusual elongated six-stranded antiparallel beta-strand needle domain containing seven iron ions coordinated by histidine residues arranged colinearly along the core of the biological unit. At the end of the tip, the three chains intertwine forming a broader head domain, which contains the putative receptor interaction site. The structure reveals a previously unknown beta-structured fibrous fold, provides insights into the remarkable stability of the fiber, and suggests a framework for mutations to expand or modulate receptor-binding specificity.

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• 5.38

  Impact points

  An adamantyl amino acid containing gramicidin S analogue with broad spectrum antibacterial activity and reduced hemolytic activity.

  Varsha V Kapoerchan, Annemiek D Knijnenburg, Miquel Niamat, Emile Spalburg, Albert J de Neeling, Peter H Nibbering, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Chemistry (Weinheim an der Bergstrasse, Germany). 10/2010; 16(40):12174-81.

  The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very ... [more] The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram-negative and Gram-positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic.

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• 3.23

  Impact points

  Understanding the key factors that control the inhibition of type II dehydroquinase by (2R)-2-benzyl-3-dehydroquinic acids.

  Antonio Peón, José M Otero, Lorena Tizón, Verónica F V Prazeres, Antonio L Llamas-Saiz, Gavin C Fox, Mark J van Raaij, Heather Lamb, Alastair R Hawkins, Federico Gago, Luis Castedo, Concepción González-Bello

  ChemMedChem. 10/2010; 5(10):1726-33.

  The binding mode of several substrate analogues, (2R)-2-benzyl-3-dehydroquinic acids 4, which are potent reversible competitive inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal struc... [more] The binding mode of several substrate analogues, (2R)-2-benzyl-3-dehydroquinic acids 4, which are potent reversible competitive inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal structures of Mycobacterium tuberculosis and Helicobacter pylori DHQ2 in complex with one of the most potent inhibitor, p-methoxybenzyl derivative 4 a, have been solved at 2.40 Å and 2.75 Å, respectively. This has allowed the resolution of the M. tuberculosis DHQ2 loop containing residues 20-25 for the first time. These structures show the key interactions of the aromatic ring in the active site of both enzymes and additionally reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. The loop conformation and the binding mode of compounds 4 b-d has been also studied by molecular dynamics simulations, which suggest that the benzyl group of inhibitors 4 prevent appropriate orientation of the catalytic tyrosine of the loop for proton abstraction and disrupts its basicity.

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• 5.15

  Impact points

  Crystallographic structure of porcine adenovirus type 4 fiber head and galectin domains.

  Pablo Guardado-Calvo, Eva M Muñoz, Antonio L Llamas-Saiz, Gavin C Fox, Richard Kahn, David T Curiel, Joel N Glasgow, Mark J van Raaij

  Journal of virology. 10/2010; 84(20):10558-68.

  Adenovirus isolate NADC-1, a strain of porcine adenovirus type 4, has a fiber containing an N-terminal virus attachment region, shaft and head domains, and a C-terminal galectin domain connected to the head by an RGD-containing sequence. The crystal structure of the head domain is similar to previou... [more] Adenovirus isolate NADC-1, a strain of porcine adenovirus type 4, has a fiber containing an N-terminal virus attachment region, shaft and head domains, and a C-terminal galectin domain connected to the head by an RGD-containing sequence. The crystal structure of the head domain is similar to previously solved adenovirus fiber head domains, but specific residues for binding the coxsackievirus and adenovirus receptor (CAR), CD46, or sialic acid are not conserved. The structure of the galectin domain reveals an interaction interface between its two carbohydrate recognition domains, locating both sugar binding sites face to face. Sequence evidence suggests other tandem-repeat galectins have the same arrangement. We show that the galectin domain binds carbohydrates containing lactose and N-acetyl-lactosamine units, and we present structures of the galectin domain with lactose, N-acetyl-lactosamine, 3-aminopropyl-lacto-N-neotetraose, and 2-aminoethyl-tri(N-acetyl-lactosamine), confirming the domain as a bona fide galectin domain.

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• 5.38

  Impact points

  Gramicidin S derivatives containing cis- and trans-morpholine amino acids (MAAs) as turn mimetics.

  Varsha V Kapoerchan, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Patricia Ferraces-Casais, Antonio L Llamas-Saiz, Mark J van Raaij, Joop van Doorn, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Chemistry (Weinheim an der Bergstrasse, Germany). 03/2010; 16(14):4259-65.

  The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and ... [more] The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational properties of the thus obtained GS analogues (6-9) was assessed by using NMR spectroscopy and X-ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8, containing the dipeptide isostere trans-MAA 4, has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and -negative bacterial strains is better than the derivatives 6, 7 and 9.

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• 29.75

  Impact points

  Spain's budget neglects research.

  Xosé Afonso Alvarez, Noemí Cabrera-Poch, Ana Canda-Sánchez, Carlos Fenollosa, Elena Piñero, Mark J van Raaij, Eva Sánchez Cobos, Ignacio Segura Pérez, Francisco J Tapiador, Ana M Torrado Agrasar

  Science (New York, N.Y.). 02/2010; 327(5969):1078-9.
• 2.44

  Impact points

  Morphogenesis of the T4 tail and tail fibers.

  Petr G Leiman, Fumio Arisaka, Mark J van Raaij, Victor A Kostyuchenko, Anastasia A Aksyuk, Shuji Kanamaru, Michael G Rossmann

  Virology journal. 01/2010; 7:355.

  Remarkable progress has been made during the past ten years in elucidating the structure of the bacteriophage T4 tail by a combination of three-dimensional image reconstruction from electron micrographs and X-ray crystallography of the components. Partial and complete structures of nine out of twent... [more] Remarkable progress has been made during the past ten years in elucidating the structure of the bacteriophage T4 tail by a combination of three-dimensional image reconstruction from electron micrographs and X-ray crystallography of the components. Partial and complete structures of nine out of twenty tail structural proteins have been determined by X-ray crystallography and have been fitted into the 3D-reconstituted structure of the "extended" tail. The 3D structure of the "contracted" tail was also determined and interpreted in terms of component proteins. Given the pseudo-atomic tail structures both before and after contraction, it is now possible to understand the gross conformational change of the baseplate in terms of the change in the relative positions of the subunit proteins. These studies have explained how the conformational change of the baseplate and contraction of the tail are related to the tail's host cell recognition and membrane penetration function. On the other hand, the baseplate assembly process has been recently reexamined in detail in a precise system involving recombinant proteins (unlike the earlier studies with phage mutants). These experiments showed that the sequential association of the subunits of the baseplate wedge is based on the induced-fit upon association of each subunit. It was also found that, upon association of gp53 (gene product 53), the penultimate subunit of the wedge, six of the wedge intermediates spontaneously associate to form a baseplate-like structure in the absence of the central hub. Structure determination of the rest of the subunits and intermediate complexes and the assembly of the hub still require further study.
• 4.80

  Impact points

  Synthesis and Biological Evaluation of New Nanomolar Competitive Inhibitors of Helicobacter pylori Type II Dehydroquinase. Structural Details of the Role of the Aromatic Moieties with Essential Residues (double dagger).

  Verónica F V Prazeres, Lorena Tizón, José M Otero, Pablo Guardado-Calvo, Antonio L Llamas-Saiz, Mark J van Raaij, Luis Castedo, Heather Lamb, Alastair R Hawkins, Concepción González-Bello

  Journal of medicinal chemistry. 11/2009;

  The shikimic acid pathway is essential to many pathogens but absent in mammals. Enzymes in its pathway are therefore appropriate targets for the development of novel antibiotics. Dehydroquinase is the third enzyme of the pathway, catalyzing the reversible dehydratation of 3-dehydroquinic acid to for... [more] The shikimic acid pathway is essential to many pathogens but absent in mammals. Enzymes in its pathway are therefore appropriate targets for the development of novel antibiotics. Dehydroquinase is the third enzyme of the pathway, catalyzing the reversible dehydratation of 3-dehydroquinic acid to form 3-dehydroshikimic acid. Here we present the synthesis of novel inhibitors with high affinity for Helicobacter pylori type II dehydroquinase and efficient inhibition characteristics. The structure of Helicobacter pylori type II dehydroquinase in complex with the most potent inhibitor shows that the aromatic functional group interacts with the catalytic Tyr22 by pi-stacking, expelling the Arg17 side chain, which is essential for catalysis, from the active site. The structure therefore explains the favorable properties of the inhibitor and will aid in design of improved antibiotics.
• 1.56

  Impact points

  Two-chaperone assisted soluble expression and purification of the bacteriophage T4 long tail fibre protein gp37.

  Sergio Galan-Bartual, Carmela Garcia-Doval, Jana Alonso, Guy Schoehn, Mark J van Raaij

  Protein expression and purification. 11/2009;

  Bacteriophage T4 recognises its host cells through its long tail fibre protein gene product (gp) 37. Gp37 is a protein containing 1026 amino acids per monomer, forming a fibrous parallel homotrimer at the distal end of the long tail fibres. The other distal half-fibre protein, gp36, is much smaller,... [more] Bacteriophage T4 recognises its host cells through its long tail fibre protein gene product (gp) 37. Gp37 is a protein containing 1026 amino acids per monomer, forming a fibrous parallel homotrimer at the distal end of the long tail fibres. The other distal half-fibre protein, gp36, is much smaller, forming a trimer of 221 amino acids per monomer. Functional and structural studies of gp37 have been hampered by the inability to produce suitable amounts of it. We produced soluble gp37 by co-expression with two bacteriophage T4-encoded chaperones in a two-vector system; co-expression with each chaperone separately did not lead to good amounts of correctly folded, trimeric protein. An expression vector for the bacteriophage T4 fibrous protein chaperone gp57 was co-transformed into bacteria with a compatible bi-cistronic expression vector containing bacteriophage T4 genes 37 and 38. A six-histidine tag is encoded amino-terminal to the gp37 gene. Recombinant trimeric gp37, containing the histidine tag and residues 12-1026 of gp37, was purified from lysed bacteria by subsequent nickel-affinity, size exclusion and strong anion exchange column chromatography. Yields of approximately 4 mg of purified protein per litre of bacterial culture were achieved. Electron microscopy confirmed the protein to form fibres around 63 nm long, presumably gp36 makes up the remaining 11 nm in the intact distal half-fibre. Purified, correctly folded, gp37 will be useful for receptor-binding studies, high-resolution structural studies and for specific binding and detection of bacteria.
• 0.55

  Impact points

  Crystallization of the head and galectin-like domains of porcine adenovirus isolate NADC-1 fibre.

  Pablo Guardado-Calvo, Antonio Llamas-Saiz, Gavin Fox, Joel Glasgow, Mark van Raaij

  Acta crystallographica. Section F, Structural biology and crystallization communications. 11/2009; 65(Pt 11):1149-1152.

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• 5.38

  Impact points

  Bisphosphine-Functionalized Cyclic Decapeptides Based on the Natural Product Gramicidin S: A Potential Scaffold for Transition-Metal Coordination.

  Sebastian Burck, Sander G A van Assema, Bas Lastdrager, J Chris Slootweg, Andreas W Ehlers, José M Otero, Bruno Dacunha-Marinho, Antonio L Llamas-Saiz, Mark Overhand, Mark J van Raaij, Koop Lammertsma

  Chemistry (Weinheim an der Bergstrasse, Germany). 08/2009;

  The natural product Gramicidin S is a promising scaffold for novel oligopeptide-based bisphosphine ligands, combining the advantageous rigid chiral backbone with the close proximity of phosphine substituents. The required unnatural, phosphine-containing, amino acid building blocks were synthesized b... [more] The natural product Gramicidin S is a promising scaffold for novel oligopeptide-based bisphosphine ligands, combining the advantageous rigid chiral backbone with the close proximity of phosphine substituents. The required unnatural, phosphine-containing, amino acid building blocks were synthesized by means of a novel protocol that involves the enantioselective alkylation of a chiral nickel Schiff base template. Three Ni complexes were prepared with different alkyl chains between the phosphine group and the alpha-carbon atom of the incorporated glycine; the absolute stereochemistry of two of them was determined by single-crystal X-ray structure analysis. By detaching the template, enantiopure L-phosphine amino acids resulted enabling the solid-phase, stepwise construction of a linear sequence of the phosphine-modified oligopeptides. On cyclization three bisphosphine-substituted Gramicidin S analogues resulted, differing only in the size and shape of the linkage between the phosphine groups and the oligopeptides backbone. Their crystal structures suggest these species to have potential as chelating ligands.

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• 2.82

  Impact points

  Synthesis and biological evaluation of asymmetric gramicidin S analogues containing modified d-phenylalanine residues.

  Matthijs van der Knaap, Eefje Engels, Henk J Busscher, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Roos H Mars-Groenendijk, Daan Noort, Gijsbert A van der Marel, Herman S Overkleeft, Mark Overhand

  Bioorganic & medicinal chemistry. 08/2009;

  The synthesis of new analogues of the cationic antimicrobial peptide gramicidin S, having a modified d-phenylalanine residue, their antibacterial properties against several Gram positive and negative strains, as well as their hemolytic activity is reported.... [more] The synthesis of new analogues of the cationic antimicrobial peptide gramicidin S, having a modified d-phenylalanine residue, their antibacterial properties against several Gram positive and negative strains, as well as their hemolytic activity is reported.

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• 3.26

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  Crystallographic structure of the {alpha}-helical triple coiled-coil domain of avian reovirus S1133 fibre.

  Pablo Guardado-Calvo, Gavin C Fox, Antonio L Llamas-Saiz, Mark J van Raaij

  The Journal of general virology. 04/2009; 90(Pt 3):672-677.

  Avian reovirus fibre, a homo-trimer of the sigmaC protein, is a minor component of the avian reovirus outer capsid. It is anchored via a short N-terminal sequence to the inner capsid lambdaC pentamer, and its protruding globular C-terminal domain is responsible for primary host cell attachment. We h... [more] Avian reovirus fibre, a homo-trimer of the sigmaC protein, is a minor component of the avian reovirus outer capsid. It is anchored via a short N-terminal sequence to the inner capsid lambdaC pentamer, and its protruding globular C-terminal domain is responsible for primary host cell attachment. We have previously solved the structure of a receptor-binding fragment in which residues 160-191 form a triple beta-spiral and 196-326 a beta-barrel head domain. Here we have expressed, purified and crystallized a major sigmaC fragment comprising residues 117-326. Its structure, which was solved by molecular replacement using the previously determined receptor-binding domain structure and refined to 1.75 A (0.175 nm) resolution, reveals an alpha-helical triple coiled-coil connected to the previously solved structure by a zinc-ion-containing linker. The coiled-coil domain contains two chloride ion binding sites, as well as specific trimerization and registration sequences. The linker may act as a functionally important hinge.