1xjb

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Crystal structure of human type 3 3alpha-hydroxysteroid dehydrogenase in complex with NADP(H), citrate and acetate molecules

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The aldo-keto reductase (AKR) human type 3 3alpha-hydroxysteroid, dehydrogenase (h3alpha-HSD3, AKR1C2) plays a crucial role in the, regulation of the intracellular concentrations of testosterone and, 5alpha-dihydrotestosterone (5alpha-DHT), two steroids directly linked to, the etiology and the progression of many prostate diseases and cancer., This enzyme also binds many structurally different molecules such as, 4-hydroxynonenal, polycyclic aromatic hydrocarbons, and indanone. To, understand the mechanism underlying the plasticity of its, substrate-binding site, we solved the binary complex structure of, h3alpha-HSD3-NADP(H) at 1.9 A resolution. During the refinement process, we found acetate and citrate molecules deeply engulfed in the, steroid-binding cavity. Superimposition of this structure with the, h3alpha-HSD3-NADP(H)-testosterone/acetate ternary complex structure, reveals that one of the mobile loops forming the binding cavity operates a, slight contraction movement against the citrate molecule while the side, chains of many residues undergo numerous conformational changes, probably, to create an optimal binding site for the citrate. These structural, changes, which altogether cause a reduction of the substrate-binding, cavity volume (from 776 A(3) in the presence of testosterone/acetate to, 704 A(3) in the acetate/citrate complex), are reminiscent of the, "induced-fit" mechanism previously proposed for the aldose reductase, another member of the AKR superfamily. We also found that the replacement, of residues Arg(301) and Arg(304), localized near the steroid-binding, cavity, significantly affects the 3alpha-HSD activity of this enzyme, toward 5alpha-DHT and completely abolishes its 17beta-HSD activity on, 4-dione. All these results have thus been used to reevaluate the binding, mode of this enzyme for androgens.

Disease

Known diseases associated with this structure: Obesity, hyperphagia, and developmental delay OMIM:[600450]

About this Structure

1XJB is a Single protein structure of sequence from Homo sapiens with ACT, SO4, NAP, EDO, CIT and BME as ligands. Active as 3-alpha-hydroxysteroid dehydrogenase (A-specific), with EC number 1.1.1.213 Full crystallographic information is available from OCA.

Reference

Comparison of crystal structures of human type 3 3alpha-hydroxysteroid dehydrogenase reveals an "induced-fit" mechanism and a conserved basic motif involved in the binding of androgen., Couture JF, de Jesus-Tran KP, Roy AM, Cantin L, Cote PL, Legrand P, Luu-The V, Labrie F, Breton R, Protein Sci. 2005 Jun;14(6):1485-97. PMID:15929998

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