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| [[Image:2h5s.gif|left|200px]] | | {{Seed}} |
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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'''
| | ===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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17017804}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17017804 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17017804}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Beta-lactamase inhibitor]] | | [[Category: Beta-lactamase inhibitor]] |
| [[Category: Drug design]] | | [[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 Mon Jul 28 12:07:44 2008'' |
