2ama
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Crystal structure of human androgen receptor ligand binding domain in complex with dihydrotestosterone
OverviewOverview
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 electrostatic interactions at both extremities of the, steroid nucleus seems mainly responsible for the higher affinity measured, experimentally for DHT over Testo. Moreover, estimation of the, ligand-receptor interaction energy through modeling confirms that even, minor modifications in ligand structure have a great impact on the, strength of these interactions. Our crystallographic data combined with, those obtained by modeling will be helpful in the design of novel, molecules with stronger affinity for the AR.
DiseaseDisease
Known diseases associated with this structure: Androgen insensitivity OMIM:[313700], Breast cancer, male, with Reifenstein syndrome OMIM:[313700], Hypospadias, perineal OMIM:[313700], Prostate cancer OMIM:[313700], Prostate cancer, susceptibility to OMIM:[313700], Spinal and bulbar muscular atrophy of Kennedy OMIM:[313700]
About this StructureAbout this Structure
2AMA is a Single protein structure of sequence from Homo sapiens with SO4 and DHT as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity., Pereira de Jesus-Tran K, Cote PL, Cantin L, Blanchet J, Labrie F, Breton R, Protein Sci. 2006 May;15(5):987-99. PMID:16641486
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