2h5s
From Proteopedia
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[[Image:2h5s.gif|left|200px]] | [[Image:2h5s.gif|left|200px]] | ||
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'''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase''' | '''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase''' | ||
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[[Category: Akker, F van den.]] | [[Category: Akker, F van den.]] | ||
[[Category: Padayatti, P S.]] | [[Category: Padayatti, P S.]] | ||
| - | [[Category: | + | [[Category: Beta-lactamase inhibitor]] |
| - | [[Category: | + | [[Category: Drug design]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:54:06 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 02:54, 4 May 2008
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. 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 Sun May 4 05:54:06 2008
