8rwp | pdb_00008rwp

KPC-2 G89D Mutant in Complex with Avibactam

spinqualitylabelsall models 8rwp, resolution 1.19Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8rwp is a 1 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.19Å Ligands: A1H3M, GOL, NXL, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BLKPC_KLEPN Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. Publication Abstract from PubMed beta-Lactamases, which hydrolyse beta-lactam antibiotics, are key determinants of antibiotic resistance. Predicting the sites and effects of distal mutations in enzymes is challenging. For beta-lactamases, the ability to make such predictions would contribute to understanding activity against, and development of, antibiotics and inhibitors to combat resistance. Here, using dynamical non-equilibrium molecular dynamics (D-NEMD) simulations combined with experiments, we demonstrate that intramolecular communication networks differ in three class A SulpHydryl Variant (SHV)-type beta-lactamases. Differences in network architecture and correlated motions link to catalytic efficiency and beta-lactam substrate spectrum. Further, the simulations identify a distal residue at position 89 in the clinically important Klebsiella pneumoniae carbapenemase 2 (KPC-2), as a participant in similar networks, suggesting that mutation at this position would modulate enzyme activity. Experimental kinetic, biophysical and structural characterisation of the naturally occurring, but previously biochemically uncharacterised, KPC-2(G89D) mutant with several antibiotics and inhibitors reveals significant changes in hydrolytic spectrum, specifically reducing activity towards carbapenems without effecting major structural or stability changes. These results show that D-NEMD simulations can predict distal sites where mutation affects enzyme activity. This approach could have broad application in understanding enzyme evolution, and in engineering of natural and de novo enzymes. Dynamical responses predict a distal site that modulates activity in an antibiotic resistance enzyme.,Beer M, Oliveira ASF, Tooke CL, Hinchliffe P, Tsz Yan Li A, Balega B, Spencer J, Mulholland AJ Chem Sci. 2024 Sep 30;15(41):17232-44. doi: 10.1039/d4sc03295k. PMID:39364073 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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