Mount Sinai Logo

Harel Weinstein

  • ADJUNCT PROFESSOR Structural and Chemical Biology
Print ProfilePrint Profile

Education

  • B.S., Technion-Israel Institute of Technology

  • M.S., Technion-Israel Institute of Technology

  • D.S., Technion-Israel Institute of Technology

Research

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

  • The study of specificity and functional trigger produced by protein binding to DNA in the regulation of gene expression, based on the structural dynamics of DNA, protein-binding properties of DNA and the structural and functional consequences of the interactions. Current work focusses on structural and dynamic determinants for the specificity and function of TATA-box binding proteins, zinc fingers, and the tumor suppressor p53. \r\n
  • Exploration of the structural context for the determinants of specificity in mechanisms of cellular signaling through ligand recognition and receptor response. Current work examines molecular structure and signal transduction mechanisms in transmembrane G-protein coupled receptors; and especially \r\n\r\n
  • receptors for the neurotransmitter serotonin: 5-HT1A, 5-HT2A and 5-HT2C; \r\n
  • ligand action and receptor structure for gonadotropin releasing hormone - GnRH, and of m,k,d-opioid receptors; \r\n
  • structure-function relations in the mechanisms of chemokine receptors as co-receptors for HIV infectivity. \r\n\r\n
  • The molecular mechanisms responsible for recognition, decoding and processing of Ca2+ signals through the EF-hand Ca-binding proteins. Ongoing work examines the structure, dynamics, function and protein engineering of Calmodulin, cardiac and skeletal TroponinC, and CalbindinD9k \r\n
  • The structural basis of molecular mechanisms in the recognition and modulation of protein-protein interactions in the signal transduction cascade. Current work is on the function of the Gbg subunit of the heterotrimeric G proteins and its modulation by peptides from various effectors. Practical considerations include structure-based design of specific "signal breaker" ligands affecting kinase and cyclase effector systems. \r\n\r\n
  • Publications

    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.

    Industry Relationships

    Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

    Dr.Weinstein is not currently required to report Industry relationships.

    Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

    Edit profile in Sinai Central

    Address

    1300 York Avenue, E-509
    New York, NY 10021

    Tel: 212-746-6358
    Fax: 212-746-8690