PDBsum entry 3vj9

Transferase

PDB id: 3vj9

Contents

Protein chain

335 a.a.

Metals

_NI

_CA

Waters ×459

PDB id:

3vj9

Name:

Transferase

Title:

Crystal structure of the human squalene synthase

Structure:

Squalene synthase. Chain: a. Fragment: unp residues 31-370. Synonym: sqs, ss, fpp:fpp farnesyltransferase, farnesyl-diphosphate farnesyltransferase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fdft1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.52Å R-factor: 0.163 R-free: 0.214

Authors:

C.I.Liu,W.Y.Jeng,W.J.Chang,A.H.J.Wang

Key ref:

C.I.Liu et al. (2012). Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase. J Biol Chem, 287, 18750-18757. PubMed id: 22474324

Date:

14-Oct-11 Release date: 11-Apr-12

Protein chain

P37268  (FDFT_HUMAN) -  Squalene synthase from Homo sapiens

Seq: 417 a.a.

Struc: 335 a.a.

Enzyme reactions

• Enzyme class: E.C.2.5.1.21 - squalene synthase.
• Pathway: Squalene and Phytoene Biosynthesis
• Reaction:
  1. 2 (2E,6E)-farnesyl diphosphate + NADPH + H⁺ = squalene + 2 diphosphate + NADP⁺
  2. 2 (2E,6E)-farnesyl diphosphate + NADH + H⁺ = squalene + 2 diphosphate + NAD⁺
• Cofactor: Mn(2+) or Mg(2+)

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

reference

J Biol Chem 287:18750-18757 (2012)

PubMed id: 22474324

Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.

C.I.Liu, W.Y.Jeng, W.J.Chang, T.P.Ko, A.H.Wang.

ABSTRACT

Zaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr(248) in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors.