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2h5s

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[[Image:2h5s.gif|left|200px]]
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{{STRUCTURE_2h5s| PDB=2h5s | SCENE= }}
{{STRUCTURE_2h5s| PDB=2h5s | SCENE= }}
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'''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase'''
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===SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 17017804 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17017804}}
==About this Structure==
==About this Structure==
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[[Category: Beta-lactamase inhibitor]]
[[Category: Beta-lactamase inhibitor]]
[[Category: Drug design]]
[[Category: Drug design]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:54:06 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 12:07:44 2008''

Revision as of 09:07, 28 July 2008

Image:2h5s.png

Template:STRUCTURE 2h5s

SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase

Template:ABSTRACT PUBMED 17017804

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

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