Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity.

Protein Science : a Publication of the Protein Society
Karine Pereira de Jésus-TranRock Breton

Abstract

Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 A resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG--which possesses the highest affinity--establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming elec...Continue Reading

References

Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Oct 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·Z Li, H A Scheraga
Feb 1, 1987·Endocrine Reviews·A D MooradianS G Korenman
Feb 1, 1981·The Journal of Clinical Endocrinology and Metabolism·I MowszowiczP Mauvais-Jarvis
Feb 1, 1995·Protein Engineering·A C WallaceJ M Thornton
Jun 1, 1995·Endocrine Reviews·C A QuigleyF S French
May 25, 1995·The New England Journal of Medicine·M E TaplinS P Balk
Oct 15, 1993·Biochemical and Biophysical Research Communications·C Ris-StalpersA O Brinkmann
Dec 15, 1995·Cell·D J MangelsdorfR M Evans
Jan 1, 1996·Nature Structural Biology·J M WurtzH Gronemeyer
Feb 1, 1996·Nature Structural Biology·J M WurtzH Gronemeyer
Feb 1, 1997·American Journal of Obstetrics and Gynecology·M Y DawoodF S Khan-Dawood
Mar 1, 1996·Frontiers in Bioscience : a Journal and Virtual Library·E T KellerC Chang
Jun 10, 1998·Nature·S P Williams, P B Sigler
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Nov 7, 1998·Molecular and Cellular Endocrinology·G Jenster
Feb 9, 1999·Vitamins and Hormones·A K RoyB Chatterjee
May 1, 1999·Proteins·T Lazaridis, M Karplus
Apr 29, 2000·The Journal of Biological Chemistry·N PoujolC Sultan
Jan 6, 2001·International Journal of Urology : Official Journal of the Japanese Urological Association·N SakaiT Murayama
Apr 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·J S SackH M Einspahr
Jul 24, 2001·Briefings in Bioinformatics·W Kaplan, T G Littlejohn
Feb 24, 2004·The American Journal of Sports Medicine·Nick A Evans
Apr 15, 2004·Endocrine Reviews·Cynthia A Heinlein, Chawnshang Chang
May 6, 2004·The Journal of Clinical Endocrinology and Metabolism·Alison K DeathDavid J Handelsman
Jun 3, 2004·Rapid Communications in Mass Spectrometry : RCM·Don H CatlinCaroline K Hatton
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Aug 26, 2004·PLoS Biology·Eugene HurRobert J Fletterick
Nov 3, 2004·Nature Reviews. Drug Discovery·Hinrich GronemeyerVincent Laudet
Nov 26, 2004·The Journal of Biological Chemistry·Eva Estébanez-PerpiñáR Kiplin Guy
Feb 3, 2005·The Journal of Endocrinology·Fernand LabrieClaude Labrie
Apr 19, 2005·Proceedings of the National Academy of Sciences of the United States of America·Casey E BohlJames T Dalton
Sep 1, 2005·The Journal of Biological Chemistry·Casey E BohlJames T Dalton

❮ Previous
Next ❯

Citations

Sep 26, 2008·Development Genes and Evolution·Michael SchubertVincent Laudet
Dec 11, 2013·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Ryan MatsudaDavid S Hage
May 17, 2012·Journal of Chemical Information and Modeling·Michał H JamrózJan Cz Dobrowolski
Aug 29, 2012·Journal of Chemical Information and Modeling·Eleonora Gianti, Randy J Zauhar
Jan 3, 2013·Journal of Chemical Information and Modeling·Huifang LiArtem Cherkasov
Sep 23, 2011·Journal of Medicinal Chemistry·Chuangxing GuoAndrea N Fanjul
Aug 18, 2012·Journal of Medicinal Chemistry·François NiquePierre Deprez
Sep 21, 2013·Journal of Medicinal Chemistry·Antonella PepeSanjay V Malhotra
May 21, 2011·SAR and QSAR in Environmental Research·L A Graham, I C Shaw
Sep 19, 2008·Molecular Biology and Evolution·Sean Michael CarrollJoseph W Thornton
May 25, 2010·Molecular Biology and Evolution·Adam M Reitzel, Ann M Tarrant
May 4, 2012·Journal of the Royal Society, Interface·Jennifer L LahtiRuss B Altman
Dec 5, 2008·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Maxime ThauvinThierry Prangé
Nov 13, 2010·International Journal of Clinical Practice·M T RosenbergM M Miner
May 4, 2010·Asian Journal of Andrology·Hao WangXiao-Meng Li
Dec 25, 2013·Journal of Computer-aided Molecular Design·Randy J ZauharWilliam J Welsh
Mar 20, 2014·Human Reproduction Update·Sofia MakievaJane E Norman
Mar 19, 2014·Endocrine-related Cancer·Christine HelsenFrank Claessens
Apr 8, 2014·Bioanalysis·Wadha AbushareedaCostas Georgakopoulos
Jan 1, 2010·Expert Opinion on Drug Discovery·Tommi H Nyrönen, Annu A Söderholm
Oct 1, 2007·Expert Opinion on Drug Discovery·Eva Estébanez-PerpiñáRobert J Fletterick
Oct 29, 2015·Molecular Biology and Evolution·Yukiko OginoTaisen Iguchi
Mar 28, 2012·The Journal of Steroid Biochemistry and Molecular Biology·Sylvain GauthierFernand Labrie
Jan 16, 2015·Journal of Medicinal Chemistry·Vincent C O Njar, Angela M H Brodie
Aug 17, 2010·Advanced Drug Delivery Reviews·Wenqing Gao
Mar 12, 2016·Bioorganic & Medicinal Chemistry Letters·Sahar KandilChristopher McGuigan
Mar 17, 2010·Bioorganic & Medicinal Chemistry Letters·Dominic BastienGervais Bérubé
Feb 19, 2015·Journal of Chemical Information and Modeling·Sirish Kaushik LakkarajuAlexander D MacKerell
Aug 19, 2008·Bioorganic & Medicinal Chemistry·Kiminori OhtaYasuyuki Endo
Oct 20, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Toine F H BoveeMichel W F Nielen
Sep 27, 2015·Journal of Computer-aided Molecular Design·Sanna P NiinivehmasOlli T Pentikäinen
Sep 1, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Solomon AsnakePer-Erik Olsson
Apr 18, 2009·Journal of Mass Spectrometry : JMS·Mario ThevisWilhelm Schänzer

❮ Previous
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