- ADJUNCT PROFESSOR Structural and Chemical Biology
Molecular Biophysics of Specificity and Signal Transduction in the Function of Proteins and DNA
Click \r\nHERE for details of recent work\r\n
\r\nMy laboratory aims to discover the structure, dynamic and electronic determinants of biological processes underlying physiological functions, through the development and application of methods in theoretical and computational biophysics. We seek a mechanistic understanding at the molecular level of detail, anchored in experimental information about structures and properties of cellular components and physiological mechanisms. Our approaches include theoretical determinations of molecular structure and properties, and computational simulations of molecular mechanisms and processes that can be studied with great accuracy.\r\n\r\n\r\n
The theoretical studies are designed to complement experimentation in providing mechanistic insights about systems of ever increasing size and complexity, and to guide pointed experimental exploration of cellular processes and functions in numerous collaborative studies. The theoretical methods we use are continuously being refined and tested in the study of biomolecular systems. They are based on methods of quantum and statistical mechanics, and implemented in novel algorithms running on supercomputers and various computational graphics machines.\r\n\r\n\r\n
A unifying theme is the understanding of mechanisms triggered by molecular recognition and leading to signal transduction. We study structural specificity and dynamics in three main areas in which such processes determine physiological mechanisms:\r\n\r\n\r\n
Strahs D, Weinstein H. Comparative modeling and molecular dynamics studies of the delta, kappa and mu opioid receptors. Protein Eng 1997 Sep; 10(9): 1019-38.
Konvicka K, Guarnieri F, Ballesteros JA, Weinstein H. A proposed structure for transmembrane segment 7 of G protein-coupled receptors incorporating an asn-Pro/Asp-Pro motif. Biophys J 1998 Aug; 75(2): 601-11.
Pardo L, Pastor N, Weinstein H. Selective binding of the TATA box-binding protein to the TATA box-containing promoter: analysis of structural and energetic factors. Biophys J 1998 Nov; 75(5): 2411-21.
Ri Y, Ballesteros JA, Abrams CK, Oh S, Verselis VK, Weinstein H, Bargiello TA. The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions. Biophys J 1999 Jun; 76(6): 2887-98.
Sankararamakrishnan R, Weinstein H. Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers. Biophys J 2000 Nov; 79(5): 2331-44.
Max M, Shanker YG, Rong M, Liu Z, Campagne F, Weinstein H, Damak S, Margolskee RF. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet 2001 May; 28(1): 58-63.The ability to taste the sweetness of carbohydrate-rich foodstuffs has a critical role in the nutritional status of humans. Although several components of bitter transduction pathways have been identified, the receptors and other sweet transduction elements remain unknown. The Sac locus in mouse, mapped to the distal end of chromosome 4 (refs. 7-9), is the major determinant of differences between sweet-sensitive and -insensitive strains of mice in their responsiveness to saccharin, sucrose and other sweeteners. To identify the human Sac locus, we searched for candidate genes within a region of approximately one million base pairs of the sequenced human genome syntenous to the region of Sac in mouse. From this search, we identified a likely candidate: T1R3, a previously unknown G protein-coupled receptor (GPCR) and the only GPCR in this region. Mouse Tas1r3 (encoding T1r3) maps to within 20,000 bp of the marker closest to Sac (ref. 9) and, like human TAS1R3, is expressed selectively in taste receptor cells. By comparing the sequence of Tas1r3 from several independently derived strains of mice, we identified a specific polymorphism that assorts between taster and non-taster strains. According to models of its structure, T1r3 from non-tasters is predicted to have an extra amino-terminal glycosylation site that, if used, would interfere with dimerization.
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Dr.Weinstein is not currently required to report Industry relationships.
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