PDBsum entry 4zgx

Oxidoreductase

PDB id: 4zgx

Contents

Protein chains

(+ 6 more) 465 a.a.

Ligands

HEM-QHC ×10

HEM ×2

Waters ×817

PDB id:

4zgx

Name:

Oxidoreductase

Title:

Structure of aldosterone synthase (cyp11b2) in complex with (+)-(r)-n- (4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl) propionamide

Structure:

Cytochrome p450 11b2, mitochondrial. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Fragment: unp residues 24-503. Synonym: aldosterone synthase,aldos,aldosterone-synthesizing enzyme, cypxib2,cytochrome p-450aldo,cytochrome p-450c18,steroid 18- hydroxylase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp11b2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.20Å R-factor: 0.214 R-free: 0.255

Authors:

A.Kuglstatter,C.Joseph

Key ref:

R.E.Martin et al. (2015). Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys. J Med Chem, 58, 8054-8065. PubMed id: 26403853 DOI: 10.1021/acs.jmedchem.5b00851

Date:

24-Apr-15 Release date: 07-Oct-15

Protein chains

P19099  (C11B2_HUMAN) -  Cytochrome P450 11B2, mitochondrial from Homo sapiens

Seq: 503 a.a.

Struc: 465 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.14.15.4 - steroid 11beta-monooxygenase.
• Reaction: a steroid + 2 reduced [adrenodoxin] + O2 + 2 H⁺ = an 11beta- hydroxysteroid + 2 oxidized [adrenodoxin] + H2O
• Cofactor: Heme-thiolate
• Enzyme class 2: E.C.1.14.15.5 - corticosterone 18-monooxygenase.
• Reaction: corticosterone + 2 reduced [adrenodoxin] + O2 + 2 H⁺ = 18-hydroxycorticosterone + 2 oxidized [adrenodoxin] + H2O

corticosterone + 2 × reduced [adrenodoxin] + O2 + 2 × H(+) = 18-hydroxycorticosterone (Bound ligand (Het Group name = HEM) matches with 46.81% similarity) + 2 × oxidized [adrenodoxin] + H2O

• Cofactor: Heme-thiolate

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: 10.1021/acs.jmedchem.5b00851

J Med Chem 58:8054-8065 (2015)

PubMed id: 26403853

Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.

R.E.Martin, J.D.Aebi, B.Hornsperger, H.J.Krebs, B.Kuhn, A.Kuglstatter, A.M.Alker, H.P.Märki, S.Müller, D.Burger, G.Ottaviani, W.Riboulet, P.Verry, X.Tan, K.Amrein, A.V.Mayweg.

ABSTRACT

Inappropriately high levels of aldosterone are associated with many serious medical conditions, including renal and cardiac failure. A focused screen hit has been optimized into a potent and selective aldosterone synthase (CYP11B2) inhibitor with in vitro activity against rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity factor of 160 against cytochrome CYP11B1 in the last species. The novel tetrahydroisoquinoline compound (+)-(R)-6 selectively reduced aldosterone plasma levels in vivo in a dose-dependent manner in db/db mice and cynomolgus monkeys. The selectivity against CYP11B1 as predicted by cellular inhibition data and free plasma fraction translated well to Synacthen challenged cynomolgus monkeys up to a dose of 0.1 mg kg(-1). This compound, displaying good in vivo potency and selectivity in mice and monkeys, is ideally suited to perform mechanistic studies in relevant rodent models and to provide the information necessary for translation to non-human primates and ultimately to man.