PDBsum entry: 2r4f

Oxidoreductase

PDB id: 2r4f

Contents

Protein chains

420 a.a. *

394 a.a. *

Ligands

SO4 ×4

RIE ×4

Waters ×1148

* Residue conservation analysis

PDB id:

2r4f

Name:

Oxidoreductase

Title:

Substituted pyrazoles as hepatselective hmg-coa reductase inhibitors

Structure:

3-hydroxy-3-methylglutaryl-coenzyme a reductase. Chain: a, b, c, d. Fragment: catalytic domain (residues 441-875). Synonym: hmg-coa reductase. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.70Å R-factor: 0.215 R-free: 0.234

Authors:

A.Pavlovsky,J.A.Pfefferkorn,M.S.Harris,B.C.Finzel

Key ref:

J.A.Pfefferkorn et al. (2008). Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia. J Med Chem, 51, 31-45. PubMed id: 18072721 DOI: 10.1021/jm070849r

Date:

31-Aug-07 Release date: 29-Apr-08

Protein chains

P04035  (HMDH_HUMAN) -  3-hydroxy-3-methylglutaryl-coenzyme A reductase

Seq: 888 a.a.

Struc: 420 a.a.*

Protein chain

P04035  (HMDH_HUMAN) -  3-hydroxy-3-methylglutaryl-coenzyme A reductase

Seq: 888 a.a.

Struc: 394 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.1.1.1.34 - Hydroxymethylglutaryl-CoA reductase (NADPH).
• Pathway: Mevalonate Biosynthesis
• Reaction: (R)-mevalonate + CoA + 2 NADP⁺ = (S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH

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

 Gene Ontology (GO) functional annotation 

• Cellular component: integral to membrane (1 term)
• Biological process: oxidation reduction (3 terms)
• Biochemical function: coenzyme binding (4 terms)

reference

DOI no: 10.1021/jm070849r

J Med Chem 51:31-45 (2008)

PubMed id: 18072721

Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia.

J.A.Pfefferkorn, C.Choi, S.D.Larsen, B.Auerbach, R.Hutchings, W.Park, V.Askew, L.Dillon, J.C.Hanselman, Z.Lin, G.H.Lu, A.Robertson, C.Sekerke, M.S.Harris, A.Pavlovsky, G.Bainbridge, N.Caspers, M.Kowala, B.D.Tait.

ABSTRACT

In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.