PDBsum entry 3h2e

Transferase/transferase inhibitor

PDB id: 3h2e

Contents

Protein chains

273 a.a. *

260 a.a. *

Ligands

SO4 ×8

B59 ×2

Waters ×256

* Residue conservation analysis

PDB id:

3h2e

Name:

Transferase/transferase inhibitor

Title:

Structural studies of pterin-based inhibitors of dihydropteroate synthase

Structure:

Dihydropteroate synthase. Chain: a, b. Engineered: yes

Source:

Bacillus anthracis str. A2012. Organism_taxid: 191218. Gene: folp, bao_0074. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.00Å R-factor: 0.204 R-free: 0.237

Authors:

M.-K.Yun,S.W.White

Key ref:

K.E.Hevener et al. (2010). Structural studies of pterin-based inhibitors of dihydropteroate synthase. J Med Chem, 53, 166-177. PubMed id: 19899766

Date:

14-Apr-09 Release date: 08-Dec-09

Protein chain

Q81VW8  (Q81VW8_BACAN) -  Dihydropteroate synthase from Bacillus anthracis

Seq: 280 a.a.

Struc: 273 a.a.

Protein chain

Q81VW8  (Q81VW8_BACAN) -  Dihydropteroate synthase from Bacillus anthracis

Seq: 280 a.a.

Struc: 260 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.5.1.15 - dihydropteroate synthase.
• Pathway: Folate Biosynthesis (late stages)
• Reaction: (7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate = 7,8- dihydropteroate + diphosphate

(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate = 7,8- dihydropteroate (Bound ligand (Het Group name = B59) matches with 48.15% similarity) + diphosphate

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

reference

J Med Chem 53:166-177 (2010)

PubMed id: 19899766

Structural studies of pterin-based inhibitors of dihydropteroate synthase.

K.E.Hevener, M.K.Yun, J.Qi, I.D.Kerr, K.Babaoglu, J.G.Hurdle, K.Balakrishna, S.W.White, R.E.Lee.

ABSTRACT

Dihydropteroate synthase (DHPS) is a key enzyme in bacterial folate synthesis and the target of the sulfonamide class of antibacterials. Resistance and toxicities associated with sulfonamides have led to a decrease in their clinical use. Compounds that bind to the pterin binding site of DHPS, as opposed to the p-amino benzoic acid (pABA) binding site targeted by the sulfonamide agents, are anticipated to bypass sulfonamide resistance. To identify such inhibitors and map the pterin binding pocket, we have performed virtual screening, synthetic, and structural studies using Bacillus anthracis DHPS. Several compounds with inhibitory activity have been identified, and crystal structures have been determined that show how the compounds engage the pterin site. The structural studies identify the key binding elements and have been used to generate a structure-activity based pharmacophore map that will facilitate the development of the next generation of DHPS inhibitors which specifically target the pterin site.