Distance geometry is a method of conformational analysis that plays a central role in the determination of protein and nucleic acid structure in solution from a wide variety of experimental data. The purpose of this research is to demonstrate the applicability of distance geometry to two other important classes of conformational problems in structural molecular biology. The first of these is the prediction of protein conformation from the crystal and/or NMR structures of homologous proteins by means of sequence alignments. The method will first be demonstrated and evaluated by predicting the structure of the flavodoxin from E. coli in parallel with the determination of its crystal structure. It will then be used to predict the structures of several interesting new and mutant proteins, including various members of the cyclophilin cis-trans isomerases and the variable domains of immunoglobulins. The second class of problems is the prediction of new ligands that bind to specific sites on proteins of known structure. The methods used here will first be developed and evaluated on the well-known dihydrofolate reductase system, and then used to search for new inhibitors for the cyclophilins. Finally, the possibility of using these methods together with the known structures of Fab/antigen complexes to predict the cross-reactivity of immunoglobulin/hapten pairs will be explored.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM047467-05
Application #
5212178
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Brazin, Kristine N; Mallis, Robert J; Boeszoermenyi, Andras et al. (2018) The T Cell Antigen Receptor ? Transmembrane Domain Coordinates Triggering through Regulation of Bilayer Immersion and CD3 Subunit Associations. Immunity 49:829-841.e6
Chhabra, Sandeep; Fischer, Patrick; Takeuchi, Koh et al. (2018) 15N detection harnesses the slow relaxation property of nitrogen: Delivering enhanced resolution for intrinsically disordered proteins. Proc Natl Acad Sci U S A 115:E1710-E1719
Zhao, Zhao; Zhang, Meng; Hogle, James M et al. (2018) DNA-Corralled Nanodiscs for the Structural and Functional Characterization of Membrane Proteins and Viral Entry. J Am Chem Soc 140:10639-10643
Hagn, Franz; Nasr, Mahmoud L; Wagner, Gerhard (2018) Assembly of phospholipid nanodiscs of controlled size for structural studies of membrane proteins by NMR. Nat Protoc 13:79-98
Nasr, Mahmoud L; Wagner, Gerhard (2018) Covalently circularized nanodiscs; challenges and applications. Curr Opin Struct Biol 51:129-134
Coote, Paul W; Robson, Scott A; Dubey, Abhinav et al. (2018) Optimal control theory enables homonuclear decoupling without Bloch-Siegert shifts in NMR spectroscopy. Nat Commun 9:3014
Ziarek, Joshua J; Baptista, Diego; Wagner, Gerhard (2018) Recent developments in solution nuclear magnetic resonance (NMR)-based molecular biology. J Mol Med (Berl) 96:1-8
Näär, Anders M (2018) miR-33: A Metabolic Conundrum. Trends Endocrinol Metab 29:667-668
Hyberts, Sven G; Robson, Scott A; Wagner, Gerhard (2017) Interpolating and extrapolating with hmsIST: seeking a tmax for optimal sensitivity, resolution and frequency accuracy. J Biomol NMR 68:139-154
Nasr, Mahmoud L; Baptista, Diego; Strauss, Mike et al. (2017) Covalently circularized nanodiscs for studying membrane proteins and viral entry. Nat Methods 14:49-52

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