PDBsum entry 3q8h

Lyase

PDB id: 3q8h

Contents

Protein chains

151 a.a. *

158 a.a. *

Ligands

AO9 ×3

EDO ×2

Metals

_ZN ×3

__K

Waters ×306

* Residue conservation analysis

PDB id:

3q8h

Name:

Lyase

Title:

Crystal structure of 2c-methyl-d-erythritol 2,4-cyclodiphosphate synthase from burkholderia pseudomallei in complex with cytidine derivative ebsi01028

Structure:

2-c-methyl-d-erythritol 2,4-cyclodiphosphate synthase. Chain: a, b, c. Synonym: mecdp-synthase, mecps. Engineered: yes

Source:

Burkholderia pseudomallei. Pseudomonas pseudomallei. Organism_taxid: 28450. Strain: 1710b. Gene: ispf, mecs, bpsl2098. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.75Å R-factor: 0.156 R-free: 0.184

Authors:

Seattle Structural Genomics Center For Infectious Disease (Ssgcid)

Key ref:

Z.Zhang et al. (2013). Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei. Bioorg Med Chem Lett, 23, 6860-6863. PubMed id: 24157367 DOI: 10.1016/j.bmcl.2013.09.101

Date:

06-Jan-11 Release date: 19-Jan-11

Protein chains

Q63T71  (ISPF_BURPS) -  2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase from Burkholderia pseudomallei (strain K96243)

Seq: 162 a.a.

Struc: 151 a.a.

Protein chain

Q63T71  (ISPF_BURPS) -  2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase from Burkholderia pseudomallei (strain K96243)

Seq: 162 a.a.

Struc: 158 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C: E.C.4.6.1.12 - 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase.
• Reaction: 4-CDP-2-C-methyl-D-erythritol 2-phosphate = 2-C-methyl-D-erythritol 2,4- cyclic diphosphate + CMP

4-CDP-2-C-methyl-D-erythritol 2-phosphate = 2-C-methyl-D-erythritol 2,4- cyclic diphosphate + CMP (Bound ligand (Het Group name = AO9) matches with 50.00% similarity)

• Cofactor: Mn(2+) or Mg(2+)

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

Key reference

DOI no: 10.1016/j.bmcl.2013.09.101

Bioorg Med Chem Lett 23:6860-6863 (2013)

PubMed id: 24157367

Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei.

Z.Zhang, S.Jakkaraju, J.Blain, K.Gogol, L.Zhao, R.C.Hartley, C.A.Karlsson, B.L.Staker, T.E.Edwards, L.J.Stewart, P.J.Myler, M.Clare, D.W.Begley, J.R.Horn, T.J.Hagen.

ABSTRACT

Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series.