TAU

TAU Trends in Research

June 1998

TAU Algorithm Reveals 3-D Structure of Hormone Receptors

Hormones transmit their chemical "messages" to cells by first binding a matching receptor molecule on the cell surface. In many cases the next step is the complex's interaction with, and activation of, a nearby enzyme. This process is often mediated by an intermediary "matchmaker" molecule, or G-Protein. G-protein-coupled receptor (GPCR) molecules have seven helical regions (domains) embedded in the cell membrane; and the nature and arrangement of these regions can be essential to binding passing hormonal signals. One such GPCR is the receptor for gonadotropin-releasing-hormone (GnRH), which helps regulate human fertility.

Although detailed knowledge of the 3-D structure of such receptors is essential to the rational design of drugs to bind to them, such structures cannot be directly determined using existing experimental methods.
New TAU computer models predict the 3-dimensional structures of G-protein receptors with unprecedented levels of speed, accuracy and visualization. Here they visualize the seven alpha-helical transmembrane regions of the human gonadotropin-releasing hormone (GnRH) receptor molecule
GnRH receptor molecule

TAU investigators Oren Becker and Zvi Naor have now developed an efficient new computer algorithm that can predict the 3-D structure of GPCR transmembrane receptor domains, using only their amino-acid sequence and some basic chemical, physical and geometrical considerations as inputs. They have already generated computer-derived 3-D models for GnRH, rhodopsin (a visual protein) and many other important GPCR, typically in less than 10 minutes each! The resulting models are geometrically and physically plausible, and correctly reproduce known helix-helix interactions. For example, mutagenesis experiments have shown that two GnRH amino acids (N-87, D-318) on different helices interact with each other, a result reproduced by the TAU model.

More recently the investigators have done physical experiments that suggest that the second and third intermediary regions (intracellular loops ICL-2 and ICL-3) that connect the GnRH molecule's transmembrane domains are the regions of the molecule responsible for the receptor's desensitization. They are now using their computerized model to investigate the dynamic behavior of these regions.

This powerful combination of experimental and computer simulation-techniques should provide much of the molecular level insight required to design hormone-mimicking drugs that can intervene in human biological processes involving, e.g., reproduction and cancer.

For further information please contact:

  1. Dr. Oren Becker
    School of Chemistry
    Raymond and Beverly Sackler Faculty of Exact Sciences
    Tel Aviv University
    P.O.B. 39040
    Tel Aviv 69978
    Israel
    Tel.: (00972) 3 / 640 7599
    Fax.: (00972) 3 / 640 9293
    E-Mail:  becker@sapphire.tau.ac.il

  2. Prof. Zvi Naor
    The Department of Biochemistry
    The George S. Wise Faculty of Life Sciences
    Tel Aviv University
    P.O.B. 39040
    Tel Aviv 69978
    Israel
    Tel.: (00972) 3 / 640 9032
    Fax.: (00972) 3 / 640 6834
    E-Mail:  naorzvi@post.tau.ac.il

TAU Trends in Research Last modified: Tue Jul 28 12:15:10 IDT 1998