PDBsum entry 3ch6

Oxidoreductase

PDB id: 3ch6

Contents

Protein chains

264 a.a. *

279 a.a. *

Ligands

NAP ×4

311 ×4

Waters ×235

* Residue conservation analysis

PDB id:

3ch6

Name:

Oxidoreductase

Title:

Crystal structure of 11beta-hsd1 double mutant (l262r, f278e) complexed with (3,3-dimethylpiperidin-1-yl)(6-(3-fluoro-4- methylphenyl)pyridin-2-yl)methanone

Structure:

Corticosteroid 11-beta-dehydrogenase isozyme 1. Chain: a, b, d, e. Fragment: 11-beta hydroxysteroid dehydrogenase. Synonym: 11-dh. 11-beta-hydroxysteroid dehydrogenase 1. 11-beta-hsd1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Gene: hsd11b1, hsd11, hsd11l. Expressed in: escherichia coli.

Resolution:

2.35Å R-factor: 0.188 R-free: 0.230

Authors:

S.Sheriff

Key ref:

H.Wang et al. (2008). Pyridine amides as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1. Bioorg Med Chem Lett, 18, 3168-3172. PubMed id: 18485702

Date:

07-Mar-08 Release date: 10-Jun-08

Protein chains

P28845  (DHI1_HUMAN) -  11-beta-hydroxysteroid dehydrogenase 1 from Homo sapiens

Seq: 292 a.a.

Struc: 264 a.a.*

Protein chains

P28845  (DHI1_HUMAN) -  11-beta-hydroxysteroid dehydrogenase 1 from Homo sapiens

Seq: 292 a.a.

Struc: 279 a.a.*

* PDB and UniProt seqs differ at 18 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B, D, E: E.C.1.1.1.146 - 11beta-hydroxysteroid dehydrogenase.
• Reaction: an 11beta-hydroxysteroid + NADP⁺ = an 11-oxosteroid + NADPH + H⁺

11beta-hydroxysteroid + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 11-oxosteroid + NADPH + H(+)

• Enzyme class 2: Chains A, B, D, E: E.C.1.1.1.201 - 7beta-hydroxysteroid dehydrogenase (NADP(+)).
• Reaction: a 7beta-hydroxysteroid + NADP⁺ = a 7-oxosteroid + NADPH + H⁺

7beta-hydroxysteroid (Bound ligand (Het Group name = 311) matches with 41.94% similarity) + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 7-oxosteroid + 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

Bioorg Med Chem Lett 18:3168-3172 (2008)

PubMed id: 18485702

Pyridine amides as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.

H.Wang, Z.Ruan, J.J.Li, L.M.Simpkins, R.A.Smirk, S.C.Wu, R.D.Hutchins, D.S.Nirschl, K.Van Kirk, C.B.Cooper, J.C.Sutton, Z.Ma, R.Golla, R.Seethala, M.E.Salyan, A.Nayeem, S.R.Krystek, S.Sheriff, D.M.Camac, P.E.Morin, B.Carpenter, J.A.Robl, R.Zahler, D.A.Gordon, L.G.Hamann.

ABSTRACT

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.