PDBsum entry 6mnc

Oxidoreductase

PDB id: 6mnc

Contents

Protein chains

276 a.a.

Ligands

PEG

J3Z

Waters ×9

PDB id:

6mnc

Name:

Oxidoreductase

Title:

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 1 complexed with estrone

Structure:

Estradiol 17-beta-dehydrogenase 1. Chain: a, b. Synonym: 17-beta-hydroxysteroid dehydrogenase type 1,17-beta-hsd 1,20 alpha-hydroxysteroid dehydrogenase,20-alpha-hsd,e2dh,placental 17- beta-hydroxysteroid dehydrogenase,short chain dehydrogenase/reductase family 28c member 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hsd17b1, e17ksr, edh17b1, edh17b2, edhb17, sdr28c1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.40Å R-factor: 0.211 R-free: 0.287

Authors:

T.Li,P.Stephen,D.W.Zhu,S.X.Lin

Key ref:

T.Li et al. (2019). Crystal structures of human 17β-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP⁺ reveal the mechanism of substrate inhibition. FEBS J, 286, 2155-2166. PubMed id: 30768851 DOI: 10.1111/febs.14784

Date:

01-Oct-18 Release date: 03-Apr-19

Protein chains

P14061  (DHB1_HUMAN) -  17-beta-hydroxysteroid dehydrogenase type 1 from Homo sapiens

Seq: 328 a.a.

Struc: 276 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.51 - 3(or 17)beta-hydroxysteroid dehydrogenase.
• Reaction:
  1. testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺
  2. testosterone + NADP⁺ = androst-4-ene-3,17-dione + NADPH + H⁺

testosterone + NAD(+) (Bound ligand (Het Group name = J3Z) matches with 95.24% similarity) = androst-4-ene-3,17-dione + NADH + H(+)

testosterone + NADP(+) (Bound ligand (Het Group name = J3Z) matches with 95.24% similarity) = androst-4-ene-3,17-dione + NADPH + H(+)

• Enzyme class 2: 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(+) = estrone (Bound ligand (Het Group name = J3Z) corresponds exactly) + NADH + H(+)

17beta-estradiol + NADP(+) = estrone (Bound ligand (Het Group name = J3Z) corresponds exactly) + 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: 10.1111/febs.14784

FEBS J 286:2155-2166 (2019)

PubMed id: 30768851

Crystal structures of human 17β-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP⁺ reveal the mechanism of substrate inhibition.

T.Li, P.Stephen, D.W.Zhu, R.Shi, S.X.Lin.

ABSTRACT

Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step in estrogen activation and is thus involved in estrogen-dependent diseases (EDDs). Unlike other 17β-HSD members, 17β-HSD1 undergoes a significant substrate-induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β-HSD1 in complex with estrone (E1) and cofactor analog NADP⁺ , demonstrating critical enzyme-substrate-cofactor interactions. These complexes revealed a reversely bound E1 in 17β-HSD1 that provides the basis of the substrate inhibition, never demonstrated in estradiol complexes. Structural analysis showed that His²²¹ is the key residue responsible for the reorganization and stabilization of the reversely bound E1, leading to the formation of a dead-end complex, which exists widely in NADP(H)-preferred enzymes for the regulation of their enzymatic activity. Further, a new inhibitor is proposed that may inhibit 17β-HSD1 through the formation of a dead-end complex. This finding indicates a simple mechanism of enzyme regulation in the physiological background and introduces a pioneer inhibitor of 17β-HSD1 based on the dead-end inhibition model for efficiently targeting EDDs. DATABASES: Coordinates and structure factors of 17β-HSD1-E1 and 17β-HSD1-E1-NADP⁺ have been deposited in the Protein Data Bank with accession code 6MNC and 6MNE respectively. ENZYMES: 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) EC 1.1.1.62.