PDBsum entry 4xvd

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4xvd

Contents

Protein chains

314 a.a.

Ligands

NAP ×2

WDV ×2

Waters ×13

PDB id:

4xvd

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

17beta-hsd5 in complex with 4-nitro-2-({4-[3-(trifluoromethyl) phenyl]piperazin-1-yl}methyl)phenol

Structure:

Aldo-keto reductase family 1 member c3. Chain: a, b. Synonym: 17-beta-hydroxysteroid dehydrogenase type 5,17-beta-hsd 5, testosterone 17-beta-dehydrogenase 5. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: akr1c3. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.81Å R-factor: 0.211 R-free: 0.259

Authors:

Y.Amano,T.Yamaguchi,T.Niimi,H.Sakashita

Key ref:

Y.Amano et al. (2015). Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding. Acta Crystallogr D Biol Crystallogr, 71, 918-927. PubMed id: 25849402 DOI: 10.1107/S1399004715002175

Date:

27-Jan-15 Release date: 15-Apr-15

Protein chains

P42330  (AK1C3_HUMAN) -  Aldo-keto reductase family 1 member C3 from Homo sapiens

Seq: 323 a.a.

Struc: 314 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.188 - prostaglandin-F synthase.
• Reaction: prostaglandin F2alpha + NADP⁺ = prostaglandin D2 + NADPH + H⁺

prostaglandin F2alpha (Bound ligand (Het Group name = NAP) corresponds exactly) + NADP(+) = prostaglandin D2 + NADPH + H(+)

• Enzyme class 2: E.C.1.1.1.210 - 3beta-(or 20alpha)-hydroxysteroid dehydrogenase.
• Reaction: 5alpha-androstane-3beta,17beta-diol + NADP⁺ = 17beta-hydroxy-5alpha- androstan-3-one + NADPH + H⁺

5alpha-androstane-3beta,17beta-diol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 17beta-hydroxy-5alpha- androstan-3-one + NADPH + H(+)

• Enzyme class 3: E.C.1.1.1.239 - 3alpha-(17beta)-hydroxysteroid dehydrogenase (NAD(+)).
• Reaction: testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺

testosterone (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) + NAD(+) = androst-4-ene-3,17-dione + NADH + H(+)

• Enzyme class 4: E.C.1.1.1.357 - 3alpha-hydroxysteroid 3-dehydrogenase.
• Reaction:
  1. a 3alpha-hydroxysteroid + NADP⁺ = a 3-oxosteroid + NADPH + H⁺
  2. a 3alpha-hydroxysteroid + NAD⁺ = a 3-oxosteroid + NADH + H⁺

3alpha-hydroxysteroid + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 3-oxosteroid + NADPH + H(+)

3alpha-hydroxysteroid + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 3-oxosteroid + NADH + H(+)

• Enzyme class 5: E.C.1.1.1.53 - 3alpha(or 20beta)-hydroxysteroid dehydrogenase.
• Reaction: androstan-3alpha,17beta-diol + NAD⁺ = 17beta-hydroxyandrostanone + NADH + H⁺

androstan-3alpha,17beta-diol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 17beta-hydroxyandrostanone + NADH + H(+)

• Enzyme class 6: E.C.1.1.1.62 - 17beta-estradiol 17-dehydrogenase.
• Reaction:
  1. 17beta-estradiol + NAD⁺ = estrone + NADH + H⁺
  2. 17beta-estradiol + NADP⁺ = estrone + NADPH + H⁺

17beta-estradiol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = estrone + NADH + H(+)

17beta-estradiol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = estrone + NADPH + H(+)

• Enzyme class 7: E.C.1.1.1.64 - testosterone 17beta-dehydrogenase (NADP(+)).
• Reaction: testosterone + NADP⁺ = androst-4-ene-3,17-dione + NADPH + H⁺

testosterone (Bound ligand (Het Group name = NAP) corresponds exactly) + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1107/S1399004715002175

Acta Crystallogr D Biol Crystallogr 71:918-927 (2015)

PubMed id: 25849402

Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding.

Y.Amano, T.Yamaguchi, T.Niimi, H.Sakashita.

ABSTRACT

Type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) is an aldo-keto reductase expressed in the human prostate which catalyzes the conversion of androstenedione to testosterone. Testosterone is converted to 5α-dihydrotestosterone, which is present at high concentrations in patients with castration-resistant prostate cancer (CRPC). Inhibition of 17β-HSD5 is therefore considered to be a promising therapy for treating CRPC. In the present study, crystal structures of complexes of 17β-HSD5 with structurally diverse inhibitors derived from high-throughput screening were determined. In the structures of the complexes, various functional groups, including amide, nitro, pyrazole and hydroxyl groups, form hydrogen bonds to the catalytic residues His117 and Tyr55. In addition, major conformational changes of 17β-HSD5 were observed following the binding of the structurally diverse inhibitors. These results demonstrate interactions between 17β-HSD5 and inhibitors at the atomic level and enable structure-based drug design for anti-CRPC therapy.