2h5s
From Proteopedia
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SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase
Overview
beta-Lactamases are one of the major causes of antibiotic resistance in, Gram negative bacteria. The continuing evolution of beta-lactamases that, are capable of hydrolyzing our most potent beta-lactams presents a vexing, clinical problem, in particular since a number of them are resistant to, inhibitors. The efficient inhibition of these enzymes is therefore of, great clinical importance. Building upon our previous structural studies, that examined tazobactam trapped as a trans-enamine intermediate in a, deacylation deficient SHV variant, we designed a novel penam sulfone, derivative that forms a more stable trans-enamine intermediate. We report, here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a, rationally designed penam sulfone, SA2-13. The compound is covalently, bound to the active site of wt SHV-1 similar to tazobactam yet forms an, additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to, stabilize the trans-enamine intermediate. Kinetic measurements show that, SA2-13, once reacted with SHV-1 beta-lactamase, is about 10-fold slower at, being released from the enzyme compared to tazobactam. Stabilizing the, trans-enamine intermediate represents a novel strategy for the rational, design of mechanism-based class A beta-lactamase inhibitors.
About this Structure
2H5S is a Single protein structure of sequence from Klebsiella pneumoniae with SA2 and MA4 as ligands. Active as Hydrolase, with EC number 3.5.2.6. Full crystallographic information is available from OCA.
Reference
Rational design of a beta-lactamase inhibitor achieved via stabilization of the trans-enamine intermediate: 1.28 A crystal structure of wt SHV-1 complex with a penam sulfone., Padayatti PS, Sheri A, Totir MA, Helfand MS, Carey MP, Anderson VE, Carey PR, Bethel CR, Bonomo RA, Buynak JD, van den Akker F, J Am Chem Soc. 2006 Oct 11;128(40):13235-42. PMID:17017804
Page seeded by OCA on Wed Nov 21 11:33:17 2007
