Exp Clin Endocrinol Diabetes 2005; 113(5): 245-247
DOI: 10.1055/s-2005-865679
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Hormone Binding to the Follicle-Stimulating Hormone Receptor - Crystal Clear!

T. Gudermann1 , P. Nurwakagari1 , D. Ben-Menahem2
  • 1Institut für Pharmakologie und Toxikologie, Fachbereich Medizin, Philipps-Universität Marburg, Germany
  • 2Department of Clinical Pharmacology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheba, Israel
Further Information

Publication History

Publication Date:
30 May 2005 (online)

Abstract

The receptors for the trophic hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyrotropin (TSH) play a central role in endocrinology. These receptors face the challenge to accommodate large heterodimeric glycoprotein ligands within their extracellular hormone-binding domain. Until recently, the mechanism of hormone binding and consequently the mode of receptor activation remained enigmatic. By solving the crystal structure of human follicle-stimulating hormone bound to the receptor's hormone binding domain, it has become clear that the follicle-stimulating hormone receptor grabs the glycoprotein hormone in a hand-clasp mode resulting in a hormone orientation perpendicular to the long axis of the ligand-binding domain. These findings have important ramifications for our understanding of the molecular mechanism of receptor activation and may provide a rational basis for the development of small, non-peptidic FSH receptor ligands.

References

  • 1 Arey B J, Deecher D C, Shen E S, Stevis P E, Meade Jr E H, Wrobel J, Frail D E, Lopez F J. Identification and characterization of a selective, nonpeptide follicle-stimulating hormone receptor antagonist.  Endocrinology. 2002;  143 3822-3829
  • 2 Ascoli M, Fanelli F, Segaloff D L. The lutropin/choriogonadotropin receptor, a 2002 perspective.  Endocr Rev. 2002;  23 141-174
  • 3 Ben-Menahem D. Single chain variants of the glycoprotein hormones and their receptors as tools to study receptor activation and for analogue design.  J Neuroendocrinol. 2004;  16 171-177
  • 4 El Tayar N. Advances in the molecular understanding of gonadotropins-receptors interactions.  Mol Cell Endocrinol. 1996;  125 65-70
  • 5 Fan Q R, Hendrickson W A. Structure of human follicle-stimulating hormone in complex with its receptor.  Nature. 2005;  433 269-277
  • 6 Fox K M, Dias J A, Van Roey P. Three-dimensional structure of human follicle-stimulating hormone.  Mol Endocrinol. 2001;  15 378-389
  • 7 Jiang X, Dreano M, Buckler D R, Cheng S, Ythier A, Wu H, Hendrickson W A, el Tayar N. Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions.  Structure. 1995;  3 1341-1353
  • 8 Kleinau G, Jaschke H, Neumann S, Lattig J, Paschke R, Krause G. Identification of a novel epitope in the thyroid-stimulating hormone receptor ectodomain acting as intramolecular signaling interface.  J Biol Chem. 2004;  279 51590-51600
  • 9 Kobe B, Deisenhofer J. The leucine-rich repeat: a versatile binding motif.  Trends Biochem Sci. 1994;  19 415-421
  • 10 Lapthorn A J, Harris D C, Littlejohn A, Lustbader J W, Canfield R E, Machin K J, Morgan F J, Isaacs N W. Crystal structure of human chorionic gonadotropin.  Nature. 1994;  369 455-461
  • 11 Moyle W R, Campbell R K, Rao S N, Ayad N G, Bernard M P, Han Y, Wang Y. Model of human chorionic gonadotropin and lutropin receptor interaction that explains signal transduction of the glycoprotein hormones.  J Biol Chem. 1995;  270 20020-20031
  • 12 Moyle W R, Xing Y, Lin W, Cao D, Myers R V, Kerrigan J E, Bernard M P. Model of glycoprotein hormone receptor ligand binding and signaling.  J Biol Chem. 2004;  279 44442-44459
  • 13 Palczewski K, Kumasaka T, Hori T, Behnke C A, Motoshima H, Fox B A, Le Trong, Teller D C, Okada T, Stenkamp R E, Yamamoto M, Miyano M. Crystal structure of rhodopsin: A G protein-coupled receptor.  Science. 2000;  289 739-745
  • 14 Pierce J G, Parsons T F. Glycoprotein hormones: structure and function.  Annu Rev Biochem. 1981;  50 465-495
  • 15 Pierce K L, Premont R T, Lefkowitz R J. Seven-transmembrane receptors.  Nat Rev Mol Cell Biol. 2002;  3 639-650
  • 16 Schöneberg T, Schulz A, Gudermann T. The structural basis of G-protein-coupled receptor function and dysfunction in human diseases.  Rev Physiol Biochem Pharmacol. 2002;  144 143-227
  • 17 van Straten N C, van Berkel T H, Demont D R, Karstens W J, Merkx R, Oosterom J, Schulz J, van Someren R G, Timmers C M, van Zandvoort P M. Identification of substituted 6-amino-4-phenyltetrahydroquinoline derivatives: potent antagonists for the follicle-stimulating hormone receptor.  J Med Chem. 2005;  48 1697-1700
  • 18 Vassart G, Pardo L, Costagliola S. A molecular dissection of the glycoprotein hormone receptors.  Trends Biochem Sci. 2004;  29 119-126
  • 19 Wu H, Lustbader J W, Liu Y, Canfield R E, Hendrickson W A. Structure of human chorionic gonadotropin at 2.6 A resolution from MAD analysis of the selenomethionyl protein.  Structure. 1994;  2 545-558

T. Gudermann

Institut für Pharmakologie und Toxikologie
Fachbereich Medizin
Philipps-Universität Marburg

Karl-von-Frisch-Straße 1

35033 Marburg

Germany

Phone: + 4964212865000

Fax: + 49 6 42 12 86 56 00

Email: guderman@staff.uni-marburg.de