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Abstract
Grant Number: 1R21NS053714-01 Project Title: A High Capacity Screen for Membrane-Active Compound(RMI)
PI Information: Name Title ENGELMAN, DONALD M. donald.engelman@yale.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): Membrane proteins are the targets of a majority of all drugs. Many of these drugs bind deeply within the non-polar region of the membrane, where transmembrane helix (TM) interactions are a dominant factor in the stability and activity of target proteins. We have developed assays that might be useful in finding molecules that specifically influence TM-TM interactions, either strengthening or weakening the association of these key elements of structure. If such molecules can be found in screens, they will provide leads for the discovery of new pharmacological agents. To investigate this possibility, we will set up screens using important proteins that we have worked with and already know to interact through their TM domains: the PDGF receptor TM, the TM of the E5 protein from Papilloma virus, the interaction of PDGFR TM with E5, and the li TM from the MHC. We will test specificity by cross comparison among different targets, by positive and negative controls with Glycophorin A TM, and by TM mutational analysis of the most specific and effective hits, where it is expected that modification of a specific binding site will alter affinity and efficacy.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
drug discovery /isolation, drug screening /evaluation, fluorescence resonance energy transfer, high throughput technology, membrane protein, protein protein interaction, technology /technique development
glycophorin, growth factor receptor, lipid bilayer membrane, major histocompatibility complex, membrane reconstitution /synthesis, platelet derived growth factor, recombinant protein, small molecule, synthetic peptide, virus protein
biotechnology, fluorescent dye /probe
Institution: YALE UNIVERSITY 47 COLLEGE STREET, STE 203 NEW HAVEN, CT 065208047 Fiscal Year: 2005 Department: MOLECULAR BIOPHYSICS & BIOCHEM (MB&B) Project Start: 30-SEP-2005 Project End: 31-AUG-2008 ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE IRG: ZNS1