6GK9

Inhibited structure of IMPDH from Pseudomonas aeruginosa

Summary for 6GK9

• Entry DOI: 10.2210/pdb6gk9/pdb
• Related: 6GJV
• Descriptor: Inosine-5'-monophosphate dehydrogenase, (5~{S})-7-azanyl-5-(4-chlorophenyl)-2,4-bis(oxidanylidene)-1,5-dihydropyrano[2,3-d]pyrimidine-6-carbonitrile, SULFATE ION, ... (4 entities in total)
• Functional Keywords: imp dehydrogenase, nucleotide biosynthesis, allosteric regulation, oxidoreductase
• Biological source: Pseudomonas aeruginosa PAO1
• Total number of polymer chains: 8
• Total formula weight: 432239.05

Authors

Labesse, G.,Alexandre, T.,Haouz, A.,Munier-Lehmann, H. (deposition date: 2018-05-18, release date: 2019-02-27, Last modification date: 2024-01-17)

Primary citation

Alexandre, T.,Lupan, A.,Helynck, O.,Vichier-Guerre, S.,Dugue, L.,Gelin, M.,Haouz, A.,Labesse, G.,Munier-Lehmann, H.
First-in-class allosteric inhibitors of bacterial IMPDHs.
Eur J Med Chem, 167:124-132, 2019

PubMed Abstract: Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now.

PubMed: 30769241
DOI: 10.1016/j.ejmech.2019.01.064

Experimental method

X-RAY DIFFRACTION (2.54 Å)