3H2O

Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase

Summary for 3H2O

• Entry DOI: 10.2210/pdb3h2o/pdb
• Related: 1TWS 1TWW 1TWZ 1TX0 1TX2 3H21 3H22 3H23 3H24 3H26 3H2A 3H2C 3H2E 3H2F 3H2M 3H2N
• Descriptor: Dihydropteroate synthase, 4-{[2-(2-amino-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)ethyl]amino}benzoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: anthracis, folate biosynthesis, dihydropteroate, pterine, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Bacillus anthracis str. A2012
• Total number of polymer chains: 2
• Total formula weight: 66808.37

Authors

Yun, M.-K.,White, S.W. (deposition date: 2009-04-14, release date: 2009-12-08, Last modification date: 2023-09-06)

Primary citation

Hevener, K.E.,Yun, M.K.,Qi, J.,Kerr, I.D.,Babaoglu, K.,Hurdle, J.G.,Balakrishna, K.,White, S.W.,Lee, R.E.
Structural studies of pterin-based inhibitors of dihydropteroate synthase.
J.Med.Chem., 53:166-177, 2010

PubMed 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.

PubMed: 19899766
DOI: 10.1021/jm900861d

Experimental method

X-RAY DIFFRACTION (2.7 Å)