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Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation.

Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YA
J Biol Chem 277 32086-93 (2002)
Related entries: 1lho, 1lhu, 1lhv

Cited: 35 times
EuropePMC logo PMID: 12065592

Abstract

The amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG) contains a single high affinity steroid-binding site. Crystal structures of this domain in complex with several different steroid ligands have revealed that estradiol occupies the SHBG steroid-binding site in an opposite orientation when compared with 5 alpha-dihydrotestosterone or C19 androgen metabolites (5 alpha-androstan-3 beta,17 beta-diol and 5 alpha-androstan-3 beta,17 alpha-diol) or the synthetic progestin levonorgestrel. Substitution of specific residues within the SHBG steroid-binding site confirmed that Ser(42) plays a key role in determining high affinity interactions by hydrogen bonding to functional groups at C3 of the androstanediols and levonorgestrel and the hydroxyl at C17 of estradiol. Among residues participating in the hydrogen bond network with hydroxy groups at C17 of C19 steroids or C3 of estradiol, Asp(65) appears to be the most important. The different binding mode of estradiol is associated with a difference in the position/orientation of residues (Leu(131) and Lys(134)) in the loop segment (Leu(131)-His(136)) that covers the steroid-binding site as well as others (Leu(171)-Lys(173) and Trp(84)) on the surface of human SHBG and may provide a basis for ligand-dependent interactions between SHBG and other macromolecules. These new crystal structures have also enabled us to construct a simple space-filling model that can be used to predict the characteristics of novel SHBG ligands.

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Reviews citing this publication (10)

  1. Diverse roles for sex hormone-binding globulin in reproduction. Hammond GL. Biol Reprod 85 431-441 (2011)
  2. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. Hammond GL. J Endocrinol 230 R13-25 (2016)
  3. A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications. Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. Endocr Rev 38 302-324 (2017)
  4. Interactions of sex hormone-binding globulin with target cells. Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA. Mol Cell Endocrinol 316 79-85 (2010)
  5. Intracrine androgen biosynthesis, metabolism and action revisited. Schiffer L, Arlt W, Storbeck KH. Mol Cell Endocrinol 465 4-26 (2018)
  6. Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. Pugeat M, Nader N, Hogeveen K, Raverot G, Déchaud H, Grenot C. Mol Cell Endocrinol 316 53-59 (2010)
  7. Structural analyses of sex hormone-binding globulin reveal novel ligands and function. Avvakumov GV, Cherkasov A, Muller YA, Hammond GL. Mol Cell Endocrinol 316 13-23 (2010)
  8. Structure/function analyses of human sex hormone-binding globulin: effects of zinc on steroid-binding specificity. Hammond GL, Avvakumov GV, Muller YA. J Steroid Biochem Mol Biol 85 195-200 (2003)
  9. Testosterone Retention Mechanism in Sertoli Cells: A Biochemical Perspective. Gill-Sharma MK. Open Biochem J 12 103-112 (2018)
  10. The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health. Alemany M. Int J Mol Sci 23 11952 (2022)

Articles citing this publication (24)

  1. Mid-life adiposity factors relate to blood-brain barrier integrity in late life. Gustafson DR, Karlsson C, Skoog I, Rosengren L, Lissner L, Blennow K. J Intern Med 262 643-650 (2007)
  2. Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W. Toxicol Sci 143 333-348 (2015)
  3. A multi-step, dynamic allosteric model of testosterone's binding to sex hormone binding globulin. Zakharov MN, Bhasin S, Travison TG, Xue R, Ulloor J, Vasan RS, Carter E, Wu F, Jasuja R. Mol Cell Endocrinol 399 190-200 (2015)
  4. Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ. Climacteric 11 Suppl 1 41-46 (2008)
  5. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Johnson N, Walker K, Gibson LJ, Orr N, Folkerd E, Haynes B, Palles C, Coupland B, Schoemaker M, Jones M, Broderick P, Sawyer E, Kerin M, Tomlinson IP, Zvelebil M, Chilcott-Burns S, Tomczyk K, Simpson G, Williamson J, Hillier SG, Ross G, Houlston RS, Swerdlow A, Ashworth A, Dowsett M, Peto J, Dos Santos Silva I, Fletcher O. J Natl Cancer Inst 104 657-669 (2012)
  6. Curariform antagonists bind in different orientations to the nicotinic receptor ligand binding domain. Wang HL, Gao F, Bren N, Sine SM. J Biol Chem 278 32284-32291 (2003)
  7. Cytoplasmic accumulation of incompletely glycosylated SHBG enhances androgen action in proximal tubule epithelial cells. Hong EJ, Sahu B, Jänne OA, Hammond GL. Mol Endocrinol 25 269-281 (2011)
  8. In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin. Thorsteinson N, Ban F, Santos-Filho O, Tabaei SM, Miguel-Queralt S, Underhill C, Cherkasov A, Hammond GL. Toxicol Appl Pharmacol 234 47-57 (2009)
  9. Binding of alkylphenols and alkylated non-phenolics to the rainbow trout (Oncorhynchus mykiss) plasma sex steroid-binding protein. Tollefsen KE. Ecotoxicol Environ Saf 68 40-48 (2007)
  10. Naturally occurring mutants inform SHBG structure and function. Wu TS, Hammond GL. Mol Endocrinol 28 1026-1038 (2014)
  11. Sea bass (Dicentrarchus labrax) sex hormone binding globulin: molecular and biochemical properties and phylogenetic comparison of its orthologues in multiple fish species. Miguel-Queralt S, Avvakumov GV, Blázquez M, Piferrer F, Hammond GL. Mol Cell Endocrinol 229 21-29 (2005)
  12. Steroid conjugates of dichloro(6-aminomethylnicotinate)platinum(II): effects on DNA, sex hormone binding globulin, the estrogen receptor, and various breast cancer cell lines. Schobert R, Bernhardt G, Biersack B, Bollwein S, Fallahi M, Grotemeier A, Hammond GL. ChemMedChem 2 333-342 (2007)
  13. Development of classification model and QSAR model for predicting binding affinity of endocrine disrupting chemicals to human sex hormone-binding globulin. Liu H, Yang X, Lu R. Chemosphere 156 1-7 (2016)
  14. Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells. Sanchez WY, de Veer SJ, Swedberg JE, Hong EJ, Reid JC, Walsh TP, Hooper JD, Hammond GL, Clements JA, Harris JM. Endocrinology 153 3179-3189 (2012)
  15. Syntheses and ligand-binding studies of 1 alpha- and 17 alpha-aminoalkyl dihydrotestosterone derivatives to human sex hormone-binding globulin. Hauptmann H, Metzger J, Schnitzbauer A, Cuilleron CY, Mappus E, Luppa PB. Steroids 68 629-639 (2003)
  16. Molecular interactions between sex hormone-binding globulin and nonsteroidal ligands that enhance androgen activity. Round P, Das S, Wu TS, Wähälä K, Van Petegem F, Hammond GL. J Biol Chem 295 1202-1211 (2020)
  17. Phylogenetic comparisons implicate sex hormone-binding globulin in "masculinization" of the female spotted hyena (Crocuta crocuta). Hammond GL, Miguel-Queralt S, Yalcinkaya TM, Underhill C, Place NJ, Glickman SE, Drea CM, Wagner AP, Siiteri PK. Endocrinology 153 1435-1443 (2012)
  18. Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states. Jasuja R, Spencer D, Jayaraj A, Peng L, Krishna M, Lawney B, Patel P, Jayaram B, Thayer KM, Beveridge DL, Bhasin S. iScience 24 102414 (2021)
  19. Expression of rabbit sex hormone-binding globulin during pregnancy and prenatal development and identification of a novel isoform. Ng KM, So MT, Lee WM. Endocrinology 146 1965-1972 (2005)
  20. Measurement-specific bioavailable testosterone using concanavalin A precipitation: comparison of calculated and assayed bioavailable testosterone. Yamamoto K, Koh E, Matsui F, Sugimoto K, Sin HS, Maeda Y, Namiki M. Int J Urol 16 894-901 (2009)
  21. Characterization and comparison of recombinant full-length ursine and human sex hormone-binding globulin. Frøbert AM, Brohus M, Toews JNC, Round P, Fröbert O, Hammond GL, Overgaard MT. FEBS Open Bio 12 362-378 (2022)
  22. Design of a specific peptide against phenolic glycolipid-1 from Mycobacterium leprae and its implications in leprosy bacilli entry. Arenas NE, Pieffet G, Rocha-Roa C, Guerrero MI. Mem Inst Oswaldo Cruz 117 e220025 (2022)
  23. Structural classification of steroid-binding sites on proteins by coarse-grained atomic environment and its correlation with their biological function. Hori-Tanaka Y, Yura K, Takai-Igarashi T, Tanaka H. Steroids 96 81-88 (2015)
  24. Integrated Computational Approaches for Inhibiting Sex Hormone-Binding Globulin in Male Infertility by Screening Potent Phytochemicals. Biswas S, Mita MA, Afrose S, Hasan MR, Islam MT, Rahman MA, Ara MJ, Chowdhury MBA, Meem HN, Mamunuzzaman M, Ahammad T, Ashik IU, Ibrahim MM, Imam MT, Hossain MA, Saleh MA. Life (Basel) 13 476 (2023)


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