5gla
Crystal structure of the class A beta-lactamase PenL-tTR10 containing 10 residues insertion in omega-loopCrystal structure of the class A beta-lactamase PenL-tTR10 containing 10 residues insertion in omega-loop
Structural highlights
FunctionPublication Abstract from PubMedThe omega loop in beta-lactamases plays a pivotal role in substrate recognition and catalysis, and some mutations in this loop affect the adaptability of the enzymes to new antibiotics. Various mutations, including substitutions, deletions, and intragenic duplications resulting in tandem repeats (TRs), have been associated with beta-lactamase substrate spectrum extension. TRs are unique among the mutations as they cause severe structural perturbations in the enzymes. We explored the process by which TRs are accommodated in order to test the adaptability of the omega loop. Structures of the mutant enzymes showed that the extra amino acid residues in the omega loop were freed outward from the enzyme, thereby maintaining the overall enzyme integrity. This structural adjustment was accompanied by disruptions of the internal alpha-helix and hydrogen bonds that originally maintained the conformation of the omega loop and the active site. Consequently, the mutant enzymes had a relaxed binding cavity, allowing for access of new substrates, which regrouped upon substrate binding in an induced-fit manner for subsequent hydrolytic reactions. Together, the data demonstrate that the design of the binding cavity, including the omega loop with its enormous adaptive capacity, is the foundation of the continuous evolution of beta-lactamases against new drugs. High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A beta-lactamase, PenL.,Yi H, Choi JM, Hwang J, Prati F, Cao TP, Lee SH, Kim HS Sci Rep. 2016 Nov 9;6:36527. doi: 10.1038/srep36527. PMID:27827433[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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