PDBsum entry 1gx1

Synthase

PDB id: 1gx1

Contents

Protein chains

157 a.a. *

Ligands

CDP ×3

SO4

Metals

_MN ×3

_ZN ×3

Waters ×299

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of 2c-Methyl-D-Erythritol 2,4- Cyclodiphosphate synthase: an essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development.

Authors

L.E.Kemp, C.S.Bond, W.N.Hunter.

Ref.

Proc Natl Acad Sci U S A, 2002, 99, 6591-6596. [DOI no: 10.1073/pnas.102679799]

PubMed id

11997478

Abstract

The crystal structure of the zinc enzyme Escherichia coli 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase in complex with cytidine 5'-diphosphate and Mn(2+) has been determined to 1.8-A resolution. This enzyme is essential in E. coli and participates in the nonmevalonate pathway of isoprenoid biosynthesis, a critical pathway present in some bacterial and apicomplexans but distinct from that used by mammals. Our analysis reveals a homotrimer, built around a beta prism, carrying three active sites, each of which is formed in a cleft between pairs of subunits. Residues from two subunits recognize and bind the nucleotide in an active site that contains a Zn(2+) with tetrahedral coordination. A Mn(2+), with octahedral geometry, is positioned between the alpha and beta phosphates acting in concert with the Zn(2+) to align and polarize the substrate for catalysis. A high degree of sequence conservation for the enzymes from E. coli, Plasmodium falciparum, and Mycobacterium tuberculosis suggests similarities in secondary structure, subunit fold, quaternary structure, and active sites. Our model will therefore serve as a template to facilitate the structure-based design of potential antimicrobial agents targeting two of the most serious human diseases, tuberculosis and malaria.

Figure 1.
Fig. 1. The reaction catalyzed by MECP synthase.

Figure 3.
Fig. 3. Fold, topology, and sequence of E. coli MECP synthase. (a) Stereo C trace color-ramped from blue (N terminus) to red (C terminus). Every 10th C is depicted by a black sphere and labeled. (b and c) Ribbon and topology diagrams of a monomer ( -sheet, purple; -helix, gold; -helix, red). (d) Sequence alignment of MECP synthase from E. coli, M. tuberculosis, and part of the P. falciparum protein. The secondary structure elements based on the E. coli enzyme structure are colored and labeled as in b. Residues whose identity is strictly conserved in all three sequences are boxed in black, conservative substitutions in gray, gray triangles mark Zn2+ ligands, and an open triangle the Mn2+-binding Glu-135. Circles mark CDP-binding residues (open and filled to distinguish subunits).