We are interested in three related problems: protein structure prediction, protein binding site characterization and the rational, structure-based design of drug inhibitors. Currently, our main project involves modeling the G protein-coupled receptors, a large family of transmembrane receptors which mediates about eighty percent of hormonal signaling and is ubiquitously involved in all aspects of cellular physiology. Our goal is to model the receptor in sufficient detail to allow the design of specific drug inhibitors acting on the intracellular loops of the receptor. Such a new class of agents would block the normal interaction with the G protein, hence interrupting the signalling pathway to downstream effectors. As a first step to this problem, we have designed a new analytical tool which is able to identify, in a rotein family, where binding surfaces to other macromolecules are likely to be located. This method, the Evolutionary Trace, has been tested and is now used to guide mutagenesis experiments in three collaborating laboratories. Its generality makes it applicable to a vast number of proteins that might be involved in pathologic processes and where a detailed understanding of the binding domain would be crucial to effective and directed structure-based drug design. For example, we have undertaken as a test to check our method against DNA-binding proteins where the interface is known, so far with good results. Thus our research may have applications to many areas other than G protein signalling. Our efforts have been greatly facilitated by the CGL resource. In particular, we use the MidasPlus program on a daily basis, as well as the sequence analysis services available through the resource.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-22
Application #
6119202
Study Section
Project Start
1999-07-01
Project End
2000-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
22
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
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Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
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Nekouzadeh, Ali; Rudy, Yoram (2016) Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. Prog Biophys Mol Biol 120:18-27
Towse, Clare-Louise; Vymetal, Jiri; Vondrasek, Jiri et al. (2016) Insights into Unfolded Proteins from the Intrinsic ?/? Propensities of the AAXAA Host-Guest Series. Biophys J 110:348-361

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