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ABSTRACT: Human erythrocyte spectrin dimers associate at the N-terminal region of alpha spectrin (alpha N) and the C-terminal region of beta-spectrin (beta C) to form tetramers. We have prepared model peptides to study the tetramerization region. Based on phasing information obtained from enzyme digests, we prepared spectrin fragments consisting of the first 156 amino-acid residues and the first 368 amino-acid residues of alpha-spectrin (Sp alpha 1-156 and Sp alpha 1-368, respectively), and found that both peptides associate with a beta-spectrin model peptide, with an affinity similar to that found in alpha beta dimer tetramerization. Spin label EPR studies show that the region consisting of residues 21-46 in alpha-spectrin is helical even in the absence of its beta-partner. Multi-dimensional nuclear magnetic resonance studies of samples with and without a spin label attached to residue 154 show that Sp alpha 1-156 consists of four helices, with the first helix unassociated with the remaining three helices, which bundle to form a triple helical coiled coil bundle. A comparison of the structures of erythrocyte spectrin with other published structures of Drosophila and chicken brain spectrin is discussed. Circular dichroism studies show that the lone helix in Sp alpha-156 associates with helices in the beta peptide to form a coiled coil bundle. Based on NMR and CD results, we suggest that the helices in Sp alpha 1-156 exhibit a looser (frayed) conformation, and that the helices convert to a tighter conformation upon association with its beta-partner. This suggestion does not rule out possible conversion of a non-structured conformation to a structured conformation in various parts of the molecule upon association. Spectrin mutations at residues 28 and 45 of alpha-spectrin have been found in patients with hereditary elliptocytosis. NMR studies were also carried out on Sp alpha 1-156R28S, Sp alpha 1-156R45S and Sp alpha 1-156R45T. A comparison of the structures of Sp alpha 1-156 and Sp alpha 1-156R28S, Sp alpha 1-156R45S and Sp alpha 1-156R45T is discussed.
Cellular & Molecular Biology Letters 02/2001; 6(3):571-85. · 1.50 Impact Factor
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ABSTRACT: We have studied the nuclear magnetic resonance solution secondary structure of the N-terminal region in human erythroid alpha-spectrin using a recombinant model peptide of alpha-spectrin consisting of residues 1-156. Pulsed field gradient diffusion coefficient measurements show that the model peptide exists as a monomer under the solution conditions used. The first 20 residues are in a random coil conformation, followed by a helix of 25 residues and then a random coil segment before the next helix. The random coil nature of this linker was confirmed by the presence of fast internal motion from (15)N relaxation measurements. The second, third and fourth helices are thought to form the triple helical bundle structural domain, consistent with previous studies. Our study shows that the N-terminal region of alpha-spectrin prior to the first structural domain forms a well behaved helix without its beta-spectrin partner.
FEBS Letters 12/2000; 485(1):81-6. · 3.54 Impact Factor
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Journal of Biomolecular NMR 01/2000; 15(4):345-6. · 3.61 Impact Factor
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ABSTRACT: Based on the structure of the thrombin--NAPAP complex, phosphinic dipeptide mimetics were designed as novel thrombin inhibitors. Synthesis and evaluation of these inhibitors revealed a promising lead with an IC50 of 0.6 microM.
Bioorganic & Medicinal Chemistry Letters 08/1999; 9(14):1957-62. · 2.55 Impact Factor
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ABSTRACT: We have previously reported that [D-Trp32]NPY and its centrally truncated analogues such as des-AA7-24[D-Trp5,32,Aoc6]NPY can competitively antagonize NPY effects on rat hypothalamus and Y1 (SK-N-MC AND HEL) cells, respectively. In continuation of this work, we performed structure-activity studies with C-terminal decapeptide sequence keeping D-Trp at position 32 to develop lower molecular weight Y1-selective antagonists. This study led to the development of des-Asn29[D-Trp28,32]NPY(27-36), which bound to both Y1 (SK-N-MC, Ki > or = 10 microM) and Y2 (SK-N-BE2, Ki = 1.01 +/- 0.03 microM) receptors. This peptide did not exhibit any agonist activity at Y1 receptors, and exhibited comparable potencies in antagonizing the effects of NPY on the synthesis of cAMP and mobilization of [Ca2+]i in HEL cells. However, in SK-N-MC cells, it was more potent in antagonizing the mobilization of [Ca2+]i than inhibition of cAMP synthesis. Substitution of Nva for Gln34 to increase the hydrophobicity without altering the carbon skeleton substantially increased Y1 affinity (Ki = 0.33 +/- 0.15 microM) and imparted Y1 selectivity (Ki for Y2 affinity = 3.16 +/- 0.50). Moreover, this peptide exhibited good antagonistic potency in HEL cells. 2D NMR studies of des-Asn29[D-Trp28,32]NPY(27-36) revealed the existence of a fairly stable loop-like structure between residues 27 and 32 and a less stable one between residues 32 and 36. The increased Y1 affinity of des-Asn29[D-Trp28,32,Nva34]NPY(27-36) may be due to the stabilization of the 32-36 loop by Nva34. It appears therefore that stabilization of the loop structures in these peptides should result in the development of more potent Y1 receptor antagonists. Our investigations also suggest that HEL cells express a homogeneous population of NPY Y1 receptors whereas SK-N-MC cells express high- and low-affinity Y1 receptors coupled to Ca2+ and cAMP, respectively.
Peptides 01/1996; 17(7):1113-8. · 2.43 Impact Factor
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ABSTRACT: BALASUBRAMANIAM, A., W. ZHAI, Z. TAO, Y. HUANG, J.E. FISCHER, P. EDEN, J.E. TAYLOR, L. KAR, S.D. SAMARASINGHE AND M.E. JOHNSON. Synthesis, structure, and antagonistic properties of des-Asn29[d-Trp28,32]NPY(27–36). PEPTIDES 17[7]1113–1118, 1996.—We have previously reported that [d-Trp32]NPY and its centrally truncated analogues such as des-AA7-24[d-Trp5,32,Aoc6]NPY can competitively antagonize NPY effects on rat hypothalamus and Y1(SK-N-MC AND HEL) cells, respectively. In continuation of this work, we performed structure-activity studies with C-terminal decapeptide sequence keeping d-Trp at position 32 to develop lower molecular weight Y1-selective antagonists. This study led to the development of des-Asn29[d-Trp28,32]NPY [27, 28](29-36), which bound to both Y1 (SK-N-MC, Ki ≥ 10 μM) and Y2 (SK-N-BE2, Ki = 1.01 ± 0.03 μM) receptors. This peptide did not exhibit any agonist activity at Y1 receptors, and exhibited comparable potencies in antagonizing the effects of NPY on the synthesis of cAMP and mobilization of [Ca2+]i in HEL cells. However, in SK-N-MC cells, it was more potent in antagonizing the mobilization of [Ca2+]i than inhibition of cAMP synthesis. Substitution of Nva for Gln34 to increase the hydrophobicity without altering the carbon skeleton substantially increased Y1 affinity (Ki = 0.33 ± 0.15 μM) and imparted Y1 selectivity (Ki for Y2 affinity = 3.16 ± 0.50). Moreover, this peptide exhibited good antagonistic potency in HEL cells. 2D NMR studies of des-Asn29[d-Trp28,32]NPY(27–36) revealed the existence of a fairly stable loop-like structure between residues 27 and 32 and a less stable one between residues 32 and 36. The increased Y1 affinity of des-Asn29[d-Trp28,32,Nva34]NPY(27–36) may be due to the stabilization of the 32–36 loop by Nva34. It appears therefore that stabilization of the loop structures in these peptides should result in the development of more potent Y1 receptor antagonists. Our investigations also suggest that HEL cells express a homogeneous population of NPY Y1 receptors whereas SK-N-MC cells express high- and low-affinity Y1 receptors coupled to Ca2+ and cAMP, respectively. Copyright © 1996 Elsevier Science Inc.
Peptides 01/1996; 17(7):1113-1118. · 2.43 Impact Factor
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ABSTRACT: Factor Xa (FXa) is an important serine protease in the blood coagulation cascade. Small synthetic competitive inhibitors of FXa are under development as potential anticoagulants. To better understand FXa structural features and molecular recognition mechanisms, we have constructed three dimensional models of FXa-inhibitor complex structures via a new search approach that samples conformational space and binding space simultaneously for DABE and DX-9065a, two bis amidinoaryl derivatives that are among the most potent and selective FXa inhibitors reported to date. We find the most probable binding modes for the two inhibitors to be a folded conformation, with one distal amidino group extending into the S1 pocket, forming a salt-bridge with FXa Asp-189, and the other positively charged group fitting into the S4 subsite, and stabilized by a cation-pi interaction. We propose as a hypothesis that the cavity-like S4 subsite formed by the three pi-faces of the aromatic residues Tyr-99, Phe-174 and Trp-215 is sufficiently rich in pi electrons that it is not only a hydrophobic pocket, but also forms a cation recognition site. This proposed cation-pi binding mechanism is one of the first proposed for enzymatic molecular recognition, and for which experimental verification can be obtained without any complicating charge compensation mechanism. Our models provide plausible explanations of the structure-activity relationships observed for these inhibitors, and suggest that cation-pi interactions may provide a novel mechanism for molecular recognition.
FEBS Letters 09/1995; 370(1-2):1-5. · 3.54 Impact Factor
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ABSTRACT: Tryptophan and 5-bromotryptophan (5-BrTrp) are relatively potent inhibitors of sickle-haemoglobin polymerization. The binding sites of these compounds to normal and sickle haemoglobin (HBA and HBS) have been suggested, but not firmly established, through the use of spin-labelled derivatives and/or computer modeling. In the present study we approached the problem by utilizing the technique of photoaffinity labelling. The cyanomet forms of HBA and HBS were subjected to photoaffinity labelling with N alpha-(4-azidotetrafluorobenzoyl)tryptophan and N alpha-(1-ethyl-2-diazomalonyl)-5-bromotryptophan respectively. Both irradiated samples of HBA and HBS were denatured, digested with trypsin, and then separated by reversed-phase HPLC. A labelled tryptic peptide was isolated from the photolabelling of HBS with N alpha-(1-ethyl-2-diazomalonyl)-5-bromotryptophan. The peptide was identified to be Val1(alpha)-Lys7(alpha), with the label attached to Val1(alpha), by virtue of amino acid analysis and sequencing, in conjunction with fast-atom-bombardment MS. The binding mode of N alpha-(1-ethyl-2-diazomalonyl)-5-bromotryptophan is proposed and its relevance to the potency of the 5-BrTrp-based anti-sickling agents is discussed.
Biochemical Journal 06/1995; 308 ( Pt 1):251-60. · 4.90 Impact Factor
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ABSTRACT: Structural comparisons of proteins in solution are often required to examine structure-functional relationships, study structural effects of mutations or distinguish between various forms of the same molecule under different conditions. A nuclear magnetic resonance (NMR) based probabilistic strategy is presented and used to study the structural differences between the two redox states of cytochrome c in solution. A probabilistic approach is employed to calculate the main chain conformations of horse ferro- and ferricytochrome c in solution, based on the published sequential d connectivity data. Conformational differences between the two oxidation states of horse cytochrome c in solution are found to be statistically significant. The largest changes in conformation are at residues Lys27, Thr28, Leu32, Gln42, Thr47, Tyr48, Thr49, Glu69, Lys72, Met80, Phe82, Ile85 and Lys86, all of which are close to the heme (within 14 A of the heme iron in the high resolution Xray structure of tuna cytochrome c). We suggest that these conformational changes may modulate local dipole moments and hence influence the interactions of cytochrome c with its physiological redox partners during the electron transfer process. The oxidation state dependent conformational differences are found to be much greater in solution than in the crystalline state, and the solution and crystal structures differ significantly in regions close to the heme. These results suggest that the highly charged nature of cytochrome c makes this protein particularly sensitive to the ionic strength of its environment and leads to differences between crystal and solution structures in the same oxidation state. In such cases, crystal structures must be used with caution for modeling molecular interactions in vivo. More generally, this analysis indicates that the determination of accurate local conformations based on nmr data can provide useful information about structure-functional aspects of proteins in solution.
Journal of biomolecular structure & dynamics 01/1995; 12(3):527-58. · 4.99 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY) is a potent orexigenic peptide. Structure-activity studies have revealed that nearly the entire sequence of NPY is required to elicit feeding responses. Therefore, in order to develop antagonistic peptides for NPY-induced feeding, we synthesized full-length analogs of NPY, substituting D-Trp in the C-terminal receptor binding region, and screened their activity in rat hypothalamus. Although [D-Trp36]NPY and [D-Trp34]NPY inhibited isoproterenol-stimulated hypothalamic membrane adenylate cyclase activity, [D-Trp32]NPY exhibited no intrinsic activity. Furthermore, [D-Trp32]NPY inhibited [125I]NPY binding to rat hypothalamic membranes with a potency comparable to that of NPY. The presence of 30 and 300 nM concentrations of [D-Trp32]NPY shifted the inhibitory dose-response curve of NPY on isoproterenol-stimulated hypothalamic membrane adenylate cyclase activity parallel to the right with comparable KB values. Moreover, in vivo experiments in rats revealed that [D-Trp32]NPY (10 micrograms) significantly attenuated the 1-h feeding response induced by NPY (1 microgram). Several other substitutions at position 32 including 2-D-Nal resulted in agonist activity, suggesting that there are strict structural requirements to induce the antagonistic property in NPY. These findings confirm that [D-Trp32]NPY is a competitive antagonist of NPY in both in vitro and in vivo systems. Analogs based on [D-Trp32]NPY may have potential clinical application, since NPY has been implicated in the pathophysiology of a number of feeding disorders including obesity, anorexia, and bulimia.
Journal of Medicinal Chemistry 04/1994; 37(6):811-5. · 5.25 Impact Factor
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ABSTRACT: HIV gp120 is specifically cleaved at a single site in the V3 loop between Arg315 and Ala316 by thrombin. Previous observations by others have indicated that binding to CD4 enhances the rate of V3 loop cleavage, and that this cleavage is a prerequisite for HIV infection. Other observations also suggest that the cleavage site is in a type II beta-turn centered at Pro313-Gly314. However, our docking experiments indicate that this conformation cannot dock to thrombin and other trypsin-like serine proteases. Thus, based on the thrombin-bound conformation of peptide substrates, we propose that CD4 binding, at a site remote from the V3 loop, induces and stabilizes a trans to cis isomerization of the highly conserved residue Pro313, and that this conformational shift is a prerequisite for cleavage by a 'thrombin-like' cellular protease and subsequent infection.
FEBS Letters 02/1994; 337(1):4-8. · 3.54 Impact Factor
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ABSTRACT: Molecular dynamics (MD) simulations have been carried out for 62.5 ps on crystal structures of deoxy sickle cell hemoglobin (HbS) and normal deoxy hemoglobin (HbA) using the CHARMM MD algorithm, with a time step of 0.001 ps. In the trajectory analysis of the 12.5-62.5 (50 ps) simulation, oscillations of the radius of gyration and solvent-accessible surface area were calculated. HbS exhibited a general contraction during the simulation, while HbA exhibited a nearly constant size. The average deviations of simulated structures from the starting structures were found to be 1.8 A for HbA and 2.3 A for HbS. The average rms amplitudes of atomic motions (atomic flexibility) were about 0.7 A HbA and about 1.0 A for HbS. The amplitudes of backbone motion correlate well with temperature factors derived from x-ray crystallography. A comparison of flexibility between the alpha- and beta-chains in both HbA and HbS indicates that the beta-chains generally exhibited greater flexibility than the alpha-chains, and that the HbS beta-chains exhibit greater flexibility in the N-terminal and D- and F-helix regions than do those of HbA. The average amplitude of backbone torsional oscillations was about 9 degrees, a value comparable with that of other simulations, with enhanced torsional oscillation occurring primarily at the ends of helices or in loop regions between helices. Comparison of atomic flexibility and torsional oscillation results suggests that the increased beta-chain flexibility results from relatively concerted motions of secondary structure elements. The increased flexibility may play an important role in HbS polymerization.(ABSTRACT TRUNCATED AT 250 WORDS)
Biopolymers 06/1993; 33(5):735-42. · 2.87 Impact Factor
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ABSTRACT: Human plasma fibronectin is a plasma glycoprotein that plays an important role in many biological processes. It consists of two identical 230-250-kDa subunits that are joined by two disulfide bonds near their carboxyl termini. Each subunit contains various binding domains composed of three types of homologous repeats. Recent work has determined the three-dimensional structures of various repeat fragments, but little is known about the three-dimensional structure of the carboxyl-terminal region. A recent NMR study of a plasmin-digested carboxyl-terminal inter-chain disulfide-linked heptapeptide dimer has proposed that the two subunits are arranged in an antiparallel fashion (An et al. (1992) Biochemistry 31, 9927-9933). We have now determined the three-dimensional structure for a substantial portion of a trypsin-digested interchain disulfide-linked 52-residue (6 kDa) fragment of the carboxyl-terminal of human plasma fibronectin (which includes the above-mentioned heptapeptide dimer) using two-dimensional NMR methods and a new strategy for NMR-based protein structure determination. The NMR data requires that the two chains in the dimer be linked in a symmetric, antiparallel arrangement. The resulting monomer conformation consists of two twisted or coiled segments, Thr3-Asn6 and Ile9-Phe12, connected by the Cys7-Pro8 residues in extended conformations, with the two monomer chains cross-linked at residues Cys7 and Cys11. The conformation of the heptapeptide dimer region differs substantially from the conformation proposed by An et al.
Journal of Biological Chemistry 05/1993; 268(12):8580-9. · 4.77 Impact Factor
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Progress in Biophysics and Molecular Biology 02/1993; 59(3):285-339. · 3.20 Impact Factor
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ABSTRACT: 1H- and 31P-n.m.r. have been used to study the interaction of the bacterial chemotaxis protein, CheY, with ATP and a variety of other phosphates in the presence and absence of bivalent metal ions. In the metal-bound conformation, CheY will bind nucleotide phosphates and phosphates in general, while in the metal-free conformation CheY loses its affinity for phosphates. In the presence of low concentrations of nitroxide-spin-labelled ATP (SL-ATP), specific proton resonances of metal-bound CheY are suppressed, indicating that ATP binds to a specific site on this metal-bound form of the protein. These studies also show that the same resonances are affected by the binding of SL-ATP and Mn2+, indicating that the phosphate- and metal-binding sites are close to each other and to Asp-57 (the site of phosphorylation in CheY). 1H- and 31P-n.m.r. studies using ATP, GTP, TTP, UTP, ADP, AMP and inorganic phosphates show that the binding is not specific for adenine, and does not involve the base directly, but is mediated primarily by the phosphate groups. Experiments with a phosphorylation mutant (Asp-13-->Asn) suggest that the observed phosphate binding and activation of CheY by phosphorylation may be related. Our results indicate that the conformational change and charge interactions brought about by the binding of a metal ion at the active site are required for CheY to interact with a phosphate. These studies also demonstrate the utility of spin-label-induced relaxation in conjunction with two-dimensional-n.m.r. measurements for exploring ligand-binding sites.
Biochemical Journal 11/1992; 287 ( Pt 2):533-43. · 4.90 Impact Factor
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ABSTRACT: CheY is a 14 kDa cytoplasmic protein that is activated by the transfer of a phosphoryl moiety to Asp-57 from phosphoCheA during signal transduction in bacterial chemotaxis. It has been established that metal ions are necessary for the autophosphorylation of CheA, the transfer of phosphate from phosphoCheA to CheY and the autodephosphorylation of phosphoCheY. In this work, paramagnetic relaxation enhancement has been used in conjunction with one- and two-dimensional n.m.r. to study the interaction of CheY with bivalent metal ions. These studies have led to the discovery of two conformations of the protein in water, corresponding to the metal-free and the metal-bound states. Binding of bivalent cations like Mg2+, Ca2+, Sr2+, Zn2+ and Mn2+ results in a conformational change from the metal-free to the metal-bound state. Preliminary assignments of the aromatic proton resonances are reported. Comparison of phase-sensitive double-quantum-filtered COSY, homonuclear Hartmann-Hahn coherence transfer and nuclear Overhauser enhancement spectra from the metal-bound and metal-free protein indicates that Trp-58, Thr-87 and Tyr-106 are particularly affected by the conformational change involved, and that this change is limited to a small number of residues. In addition, homonuclear Hartmann-Hahn coherence transfer experiments with paramagnetic Mn2+ show significant suppression of cross-peaks associated with Trp-58 and several neighbouring residues. Comparison of the distances estimated using n.m.r. with the CheY crystal structure indicates that the n.m.r. results are consistent with bivalent metal binding at the cluster of aspartic acid residues that includes Asp-13 and Asp-57. These studies also demonstrate the utility of paramagnetic metal-induced relaxation in conjunction with two-dimensional n.m.r. measurements for exploring ligand-binding sites.
Biochemical Journal 11/1992; 287 ( Pt 2):521-31. · 4.90 Impact Factor
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ABSTRACT: Gamma-turns are regular secondary structure elements, found with some frequency in small peptides, that have been implicated in the biologically active conformations of several systems. This report describes the design, synthesis and conformational analysis of a non-peptide gamma-turn mimetic. Low energy conformations of the mimetic system exhibit good conformational agreement with an experimentally observed peptide gamma-turn. The mimetics were incorporated into the nonapeptide bradykinin, for which a gamma-turn, formed by residues Ser 6 to Phe 8, has been hypothesized to be a bioactive conformation. The results indicate that a bioactive conformation of bradykinin may include a reverse turn at this position.
Biochemical and Biophysical Research Communications 10/1992; 187(2):999-1006. · 2.48 Impact Factor
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ABSTRACT: Poor bioavailability, rapid degradation, antigenicity, and high cost often limit the use of proteinaceous pharmaceuticals. One goal of structural biochemistry is the reduction of complex molecules to small functional units that are amenable to high-resolution structural analysis and rapid modification. The dissection of complex proteins into small synthetic conformationally restricted components is an important step in the design of low molecular weight nonpeptides that mimic the activity of the native protein. We have developed a reverse-turn mimetic system to explore peptide and protein structure-function relationships. We now report the design and synthesis of a small molecule (M(r) 810, as its trifluoroacetate salt), water soluble, proteolytically stable mimetic of residues Gln40-Thr45 of the complementarity-determining 2-like region of CD4. This mimetic has a low micromolar Kd for human T-lymphotropic virus type IIIB gp120 and reduces syncytium formation.
Proceedings of the National Academy of Sciences 08/1992; 89(13):5872-6. · 9.68 Impact Factor
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ABSTRACT: Recent work has suggested that the thrombin-bound conformation of fibrinopeptide A exhibits a strand-turn-strand motif, with a beta-turn centered at residues Glu-11 and Gly-12. Our molecular modeling analysis indicates that the published fibrinopeptide conformation cannot bind reasonably to thrombin but that reorientation of two residues by alignment with bovine pancreatic trypsin inhibitor provides a good fit within the deep thrombin cleft and satisfies all of the experimental nuclear Overhauser effect data. Based on this analysis, we have successfully designed and synthesized hybrid peptide mimetic substrates and inhibitors that mimic the proposed beta-turn structure. The results indicate that the turn conformation is an important aspect of thrombin specificity and that our turn mimetic design successfully mimics the thrombin-bound conformation of fibrinopeptide.
Proceedings of the National Academy of Sciences 04/1992; 89(5):1705-9. · 9.68 Impact Factor
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ABSTRACT: The binding sites of indole-based gelation inhibitors with sickle cell hemoglobin were investigated by two parallel theoretical approaches. A geometric approach originated by Kuntz and co-workers uses a spatial buildup scheme to locate potential binding regions, while a hybrid grid/geometric search method searches for specific indole ring binding pockets over the hemoglobin surface. The binding sites derived from these calculations were tested for their ability to accommodate indole rings by means of accessibility calculations with probes of various radii. These sites were further scanned for van der Waals' overlap and electrostatic interactions. A full 5BrTrp residue was built in each indole ring binding site, and its conformational energy of association with sickle hemoglobin was calculated at that site. Our theoretical results predict a total of 14 potential binding regions, including all of the sites observed from X-ray crystallography, and sites that are consistent with solution nuclear magnetic resonance studies.
Journal of Molecular Biology 03/1992; 223(3):791-800. · 4.00 Impact Factor
