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4ay9

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4ay9, resolution 2.50Å ()
Ligands:
Non-Standard Residues:
Related: 1fl7, 1xun, 1xwd


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor

Publication Abstract from PubMed

FSH, a glycoprotein hormone, and the FSH receptor (FSHR), a G protein-coupled receptor, play central roles in human reproduction. We report the crystal structure of FSH in complex with the entire extracellular domain of FSHR (FSHR(ED)), including the enigmatic hinge region that is responsible for signal specificity. Surprisingly, the hinge region does not form a separate structural unit as widely anticipated but is part of the integral structure of FSHR(ED). In addition to the known hormone-binding site, FSHR(ED) provides interaction sites with the hormone: a sulfotyrosine (sTyr) site in the hinge region consistent with previous studies and a potential exosite resulting from putative receptor trimerization. Our structure, in comparison to others, suggests FSHR interacts with its ligand in two steps: ligand recruitment followed by sTyr recognition. FSH first binds to the high-affinity hormone-binding subdomain of FSHR and reshapes the ligand conformation to form a sTyr-binding pocket. FSHR then inserts its sTyr (i.e., sulfated Tyr335) into the FSH nascent pocket, eventually leading to receptor activation.

Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor., Jiang X, Liu H, Chen X, Chen PH, Fischer D, Sriraman V, Yu HN, Arkinstall S, He X, Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12491-6. Epub 2012 Jul 16. PMID:22802634

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[FSHR_HUMAN] Defects in FSHR are a cause of ovarian dysgenesis type 1 (ODG1) [MIM:233300]; also known as premature ovarian failure or gonadal dysgenesis XX type or XX gonadal dysgenesis (XXGD) or hereditary hypergonadotropic ovarian failure or hypergonadotropic ovarian dysgenesis with normal karyotype. ODG1 is an autosomal recessive disease characterized by primary amenorrhea, variable development of secondary sex characteristics, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).[1][2][3][4][5][6][7] Defects in FSHR are a cause of ovarian hyperstimulation syndrome (OHSS) [MIM:608115]. OHSS is a disorder which occurs either spontaneously or most often as an iatrogenic complication of ovarian stimulation treatments for in vitro fertilization. The clinical manifestations vary from abdominal distention and discomfort to potentially life-threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Pathologic features of this syndrome include the presence of multiple serous and hemorrhagic follicular cysts lined by luteinized cells, a condition called hyperreactio luteinalis.[8][9][10][11][12] [FSHB_HUMAN] Defects in FSHB are a cause of isolated follicle-stimulating hormone deficiency (IFSHD) [MIM:229070]. Selective follicle-stimulating hormone deficiency is an uncommon cause of infertility, producing amenorrhea and hypogonadism in women and oligo or azoospermia with normal testosterone levels in normally virilised men.[13][14][15]

Function

[FSHR_HUMAN] Receptor for follicle-stimulating hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. [FSHB_HUMAN] Stimulates development of follicle and spermatogenesis in the reproductive organs.

About this Structure

4ay9 is a 9 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Jiang X, Liu H, Chen X, Chen PH, Fischer D, Sriraman V, Yu HN, Arkinstall S, He X. Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12491-6. Epub 2012 Jul 16. PMID:22802634 doi:10.1073/pnas.1206643109
  1. Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehvaslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995 Sep 22;82(6):959-68. PMID:7553856
  2. Jiang M, Aittomaki K, Nilsson C, Pakarinen P, Iitia A, Torresani T, Simonsen H, Goh V, Pettersson K, de la Chapelle A, Huhtaniemi I. The frequency of an inactivating point mutation (566C-->T) of the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybridization and time-resolved fluorometry. J Clin Endocrinol Metab. 1998 Dec;83(12):4338-43. PMID:9851774
  3. Beau I, Touraine P, Meduri G, Gougeon A, Desroches A, Matuchansky C, Milgrom E, Kuttenn F, Misrahi M. A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. J Clin Invest. 1998 Oct 1;102(7):1352-9. PMID:9769327 doi:10.1172/JCI3795
  4. Touraine P, Beau I, Gougeon A, Meduri G, Desroches A, Pichard C, Detoeuf M, Paniel B, Prieur M, Zorn JR, Milgrom E, Kuttenn F, Misrahi M. New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype. Mol Endocrinol. 1999 Nov;13(11):1844-54. PMID:10551778
  5. Doherty E, Pakarinen P, Tiitinen A, Kiilavuori A, Huhtaniemi I, Forrest S, Aittomaki K. A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. J Clin Endocrinol Metab. 2002 Mar;87(3):1151-5. PMID:11889179
  6. Allen LA, Achermann JC, Pakarinen P, Kotlar TJ, Huhtaniemi IT, Jameson JL, Cheetham TD, Ball SG. A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics. Hum Reprod. 2003 Feb;18(2):251-6. PMID:12571157
  7. Meduri G, Touraine P, Beau I, Lahuna O, Desroches A, Vacher-Lavenu MC, Kuttenn F, Misrahi M. Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies. J Clin Endocrinol Metab. 2003 Aug;88(8):3491-8. PMID:12915623
  8. Vasseur C, Rodien P, Beau I, Desroches A, Gerard C, de Poncheville L, Chaplot S, Savagner F, Croue A, Mathieu E, Lahlou N, Descamps P, Misrahi M. A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med. 2003 Aug 21;349(8):753-9. PMID:12930927 doi:http://dx.doi.org/10.1056/NEJMoa030065
  9. Smits G, Olatunbosun O, Delbaere A, Pierson R, Vassart G, Costagliola S. Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. N Engl J Med. 2003 Aug 21;349(8):760-6. PMID:12930928 doi:http://dx.doi.org/10.1056/NEJMoa030064
  10. Montanelli L, Delbaere A, Di Carlo C, Nappi C, Smits G, Vassart G, Costagliola S. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. J Clin Endocrinol Metab. 2004 Apr;89(4):1255-8. PMID:15080154
  11. De Leener A, Montanelli L, Van Durme J, Chae H, Smits G, Vassart G, Costagliola S. Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J Clin Endocrinol Metab. 2006 Feb;91(2):555-62. Epub 2005 Nov 8. PMID:16278261 doi:jc.2005-1580
  12. De Leener A, Caltabiano G, Erkan S, Idil M, Vassart G, Pardo L, Costagliola S. Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome. Hum Mutat. 2008 Jan;29(1):91-8. PMID:17721928 doi:10.1002/humu.20604
  13. Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, Casagrande S, Tedeschini G, Benedetti A, Chatterjee VK. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993 Sep;5(1):83-6. PMID:8220432 doi:http://dx.doi.org/10.1038/ng0993-83
  14. Layman LC, Lee EJ, Peak DB, Namnoum AB, Vu KV, van Lingen BL, Gray MR, McDonough PG, Reindollar RH, Jameson JL. Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene. N Engl J Med. 1997 Aug 28;337(9):607-11. PMID:9271483 doi:10.1056/NEJM199708283370905
  15. Matthews C, Chatterjee VK. Isolated deficiency of follicle-stimulating hormone re-revisited. N Engl J Med. 1997 Aug 28;337(9):642. PMID:9280841 doi:10.1056/NEJM199708283370918

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