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Pil Seok Chae,
Rohini R Rana, Kamil Gotfryd,
Søren G F Rasmussen,
Andrew C Kruse,
Kyung Ho Cho,
Stefano Capaldi,
Emil Carlsson,
Brian Kobilka,
Claus J Loland,
Ulrik Gether,
Surajit Banerjee,
Bernadette Byrne,
John K Lee,
Samuel H Gellman
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ABSTRACT: The development of a new class of surfactants for membrane protein manipulation, "GNG amphiphiles", is reported. These amphiphiles display promising behavior for membrane proteins, as demonstrated recently by the high resolution structure of a sodium-pumping pyrophosphatase reported by Kellosalo et al. (Science, 2012, 337, 473).
Chemical Communications 11/2012; · 6.17 Impact Factor
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ABSTRACT: Abstract Membrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led to the elucidation of over 250 unique membrane protein crystal structures. The aim of the European Drug Initiative for Channels and Transporter (EDICT) project is to use the structures of clinically significant membrane proteins for the development of lead molecules. One of the approaches used to achieve this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family.
Molecular Membrane Biology 08/2012; · 2.86 Impact Factor
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Pil Seok Chae,
Søren G F Rasmussen,
Rohini R Rana, Kamil Gotfryd,
Andrew C Kruse,
Aashish Manglik,
Kyung Ho Cho,
Shailika Nurva,
Ulrik Gether,
Lan Guan,
Claus J Loland,
Bernadette Byrne,
Brian K Kobilka,
Samuel H Gellman
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ABSTRACT: Non-traditional amphiphiles: Conferring aqueous solubility on membrane proteins generally requires the use of a detergent or other amphiphilic agent. A new class of amphiphiles was synthesized, based on steroidal lipophilic groups, and evaluated with several membrane proteins. The results show that the new amphiphile, "glyco-diosgenin" (GDN; see figure), confers enhanced stability to a variety of membrane proteins in solution relative to popular conventional detergents, such as dodecylmaltoside (DDM).
Chemistry 06/2012; 18(31):9485-90. · 5.93 Impact Factor
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Pil Seok Chae, Kamil Gotfryd,
Jennifer Pacyna,
Larry J W Miercke,
Søren G F Rasmussen,
Rebecca A Robbins,
Rohini R Rana,
Claus J Loland,
Brian Kobilka,
Robert Stroud,
Bernadette Byrne,
Ulrik Gether,
Samuel H Gellman
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ABSTRACT: We describe a new type of synthetic amphiphile that is intended to support biochemical characterization of intrinsic membrane proteins. Members of this new family displayed favorable behavior with four of five membrane proteins tested, and these amphiphiles formed relatively small micelles.
Journal of the American Chemical Society 11/2010; 132(47):16750-2. · 9.91 Impact Factor
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Pil Seok Chae,
Søren G F Rasmussen,
Rohini R Rana, Kamil Gotfryd,
Richa Chandra,
Michael A Goren,
Andrew C Kruse,
Shailika Nurva,
Claus J Loland,
Yves Pierre,
David Drew,
Jean-Luc Popot,
Daniel Picot,
Brian G Fox,
Lan Guan,
Ulrik Gether,
Bernadette Byrne,
Brian Kobilka,
Samuel H Gellman
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ABSTRACT: The understanding of integral membrane protein (IMP) structure and function is hampered by the difficulty of handling these proteins. Aqueous solubilization, necessary for many types of biophysical analysis, generally requires a detergent to shield the large lipophilic surfaces of native IMPs. Many proteins remain difficult to study owing to a lack of suitable detergents. We introduce a class of amphiphiles, each built around a central quaternary carbon atom derived from neopentyl glycol, with hydrophilic groups derived from maltose. Representatives of this maltose-neopentyl glycol (MNG) amphiphile family show favorable behavior relative to conventional detergents, as manifested in multiple membrane protein systems, leading to enhanced structural stability and successful crystallization. MNG amphiphiles are promising tools for membrane protein science because of the ease with which they may be prepared and the facility with which their structures may be varied.
Nature Methods 10/2010; 7(12):1003-8. · 19.28 Impact Factor
