3G31

CTX-M-9 class A beta-lactamase complexed with compound 4 (GF1)

Summary for 3G31

• Entry DOI: 10.2210/pdb3g31/pdb
• Related: 3G2Y 3G2Z 3G30 3G32 3G34 3G35
• Descriptor: Beta-lactamase CTX-M-9a, (2S)-2-[(3aR,4R,7S,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl]propanoic acid, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: ctx-m, beta-lactamase, molecular docking, fragment, inhibitor, antibiotic resistance, hydrolase, plasmid, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 57555.59

Authors

Chen, Y.,Shoichet, B.K. (deposition date: 2009-02-01, release date: 2009-03-24, Last modification date: 2023-09-06)

Primary citation

Chen, Y.,Shoichet, B.K.
Molecular docking and ligand specificity in fragment-based inhibitor discovery
Nat.Chem.Biol., 5:358-364, 2009

PubMed Abstract: Fragment screens have successfully identified new scaffolds in drug discovery, often with relatively high hit rates (5%) using small screening libraries (1,000-10,000 compounds). This raises two questions: would other noteworthy chemotypes be found were one to screen all commercially available fragments (>300,000), and does the success rate imply low specificity of fragments? We used molecular docking to screen large libraries of fragments against CTX-M beta-lactamase. We identified ten millimolar-range inhibitors from the 69 compounds tested. The docking poses corresponded closely to the crystallographic structures subsequently determined. Notably, these initial low-affinity hits showed little specificity between CTX-M and an unrelated beta-lactamase, AmpC, which is unusual among beta-lactamase inhibitors. This is consistent with the idea that the high hit rates among fragments correlate to a low initial specificity. As the inhibitors were progressed, both specificity and affinity rose together, yielding to our knowledge the first micromolar-range noncovalent inhibitors against a class A beta-lactamase.

PubMed: 19305397
DOI: 10.1038/nchembio.155

Experimental method

X-RAY DIFFRACTION (1.7 Å)