PDBsum entry 2z4y

Transferase/transferase inhibitor

PDB id: 2z4y

Contents

Protein chains

291 a.a. *

Ligands

252 ×3

Metals

_MG

Waters ×391

* Residue conservation analysis

PDB id:

2z4y

Name:

Transferase/transferase inhibitor

Title:

S. Cerevisiae geranylgeranyl pyrophosphate synthase in complex with magnesium and bph-252

Structure:

Geranylgeranyl pyrophosphate synthetase. Chain: a, b. Synonym: ggpp synthetase, ggppsase, geranylgeranyl diphosphate synthase, bet2 suppressor protein 1. Ec: 2.5.1.30, 2.5.1.1, 2.5.1.10, 2.5.1.29. Engineered: yes

Source:

Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.181 R-free: 0.232

Authors:

C.K.-M.Chen,R.T.Guo,M.Hudock,R.Cao,E.Oldfield,A.H.-J.Wang

Key ref:

C.K-M Chen et al. (2008). Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J Med Chem, 51, 5594-5607. PubMed id: 18800762

Date:

26-Jun-07 Release date: 01-Jul-08

Protein chains

Q12051  (GGPPS_YEAST) -  Geranylgeranyl pyrophosphate synthase BTS1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 335 a.a.

Struc: 291 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.5.1.1 - dimethylallyltranstransferase.
• Pathway: Terpenoid biosynthesis
• Reaction: isopentenyl diphosphate + dimethylallyl diphosphate = (2E)- geranyl diphosphate + diphosphate
• Enzyme class 2: E.C.2.5.1.10 - (2E,6E)-farnesyl diphosphate synthase.

Pathway:

• Reaction: isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate
• Enzyme class 3: E.C.2.5.1.29 - geranylgeranyl diphosphate synthase.

Pathway:

• Reaction: isopentenyl diphosphate + (2E,6E)-farnesyl diphosphate = (2E,6E,10E)- geranylgeranyl diphosphate + diphosphate

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

J Med Chem 51:5594-5607 (2008)

PubMed id: 18800762

Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation.

C.K-M Chen, M.P.Hudock, Y.Zhang, R.T.Guo, R.Cao, J.H.No, P.H.Liang, T.P.Ko, T.H.Chang, S.C.Chang, Y.Song, J.Axelson, A.Kumar, A.H.Wang, E.Oldfield.

ABSTRACT

We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three "V-shaped" bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.