4n9l

crystal structure of beta-lactamse PenP_E166S in complex with meropenem

spinqualitylabelsall models 4n9l, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4n9l is a 2 chain structure with sequence from Bacillus licheniformis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: DWZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BLAC_BACLI Publication Abstract from PubMed Most class A beta-lactamases cannot hydrolyze carbapenem antibiotics effectively. The molecular mechanism of this catalytic inefficiency has been attributed to the unique stereochemistry of carbapenems, including their 6-alpha-hydroxyethyl side chain and the transition between two tautomeric states when bound at the active site. Previous studies have shown that the 6-alpha-hydroxyethyl side chain of carbapenems can interfere with catalysis by forming hydrogen bonds with the deacylation water molecule to reduce its nucleophilicity. Here our studies of a class A noncarbapenemase PenP demonstrate that substituting the general base residue Glu166 with Ser or other residues leads to a significant enhancement of the acylation kinetics by approximately 100-500 times toward carbapenems like meropenem. The structures of PenP and Glu166Ser both in apo form and in complex with meropenem reveal that Glu166 is critical for the formation of a hydrogen bonding network within the active site that locks Asn170 in an orientation to impose steric clash with the 6-alpha-hydroxyethyl side chain of meropenem. The Glu166Ser substitution weakens this network and enables Asn170 to adopt an alternative conformation to avoid steric clash and accommodate faster acylation kinetics. Furthermore, the weakened hydrogen bonding network caused by the Glu166Ser substitution allows the 6-alpha-hydroxyethyl moiety to adopt a catalytically favorable orientation as seen in class A carbapenemases. In summary, our data identify a previously unreported role of the universally conserved general base residue Glu166 in impeding the proper binding of carbapenems by restricting their 6-alpha-hydroxyethyl group. Perturbing the General Base Residue Glu166 in the Active Site of Class A beta-Lactamase Leads to Enhanced Carbapenem Binding and Acylation.,Pan X, Wong WT, He Y, Jiang Y, Zhao Y Biochemistry. 2014 Aug 26;53(33):5414-23. doi: 10.1021/bi401609h. Epub 2014 Aug, 15. PMID:25020031 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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