8tmt

Crystal structure of KPC-44 carbapenemase in complex with vaborbactam

spinqualitylabelsall models 8tmt, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tmt 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 1.7Å Ligands: 4D6, EDO, GOL, LI, NA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A4Y5JTU1_KLEPN Publication Abstract from PubMed Klebsiella pneumoniae carbapenemase 2 (KPC-2) is an important source of drug resistance as it can hydrolyze and inactivate virtually all beta-lactam antibiotics. KPC-2 is potently inhibited by avibactam via formation of a reversible carbamyl linkage of the inhibitor with the catalytic serine of the enzyme. However, the use of avibactam in combination with ceftazidime (CAZ-AVI) has led to the emergence of CAZ-AVI resistant variants of KPC-2 in clinical settings. One such variant, KPC-44, bears a 15 amino-acid duplication in one of the active site loops (270-loop). Here, we show that the KPC-44 variant exhibits higher catalytic efficiency in hydrolyzing ceftazidime, lower efficiency towards imipenem and meropenem, and a similar efficiency in hydrolyzing ampicillin, when compared to the wild-type KPC-2 enzyme. In addition, the KPC-44 variant enzyme exhibits 12-fold lower avibactam carbamylation efficiency than the KPC-2 enzyme. An X-ray crystal structure of KPC-44 showed that the 15 amino acid duplication results in an extended and partially disordered 270-loop and also changes the conformation of the adjacent 240-loop, which in turn has altered interactions with the active-site omega loop. Furthermore, a structure of KPC-44 with avibactam revealed that formation of the covalent complex results in further disorder in the 270-loop, suggesting that rearrangement of the 270-loop of KPC-44 facilitates avibactam carbamylation. These results suggest that the duplication of 15 amino acids in the KPC-44 enzyme leads to resistance to CAZ-AVI by modulating the stability and conformation of the 270-, 240-, and omega-loops. Klebsiella pneumoniae carbapenemase variant 44 (KPC-44) acquires ceftazidime-avibactam resistance by altering the conformation of active site loops.,Sun Z, Lin H, Hu L, Neetu N, Sankaran B, Wang J, Prasad BVV, Palzkill T J Biol Chem. 2023 Nov 22:105493. doi: 10.1016/j.jbc.2023.105493. PMID:38000656 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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