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| - | [[Image:2a49.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2a49| PDB=2a49 | SCENE= }} | | {{STRUCTURE_2a49| PDB=2a49 | SCENE= }} |
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| - | '''Crystal structure of clavulanic acid bound to E166A variant of SHV-1 beta-lactamase'''
| + | ===Crystal structure of clavulanic acid bound to E166A variant of SHV-1 beta-lactamase=== |
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| - | ==Overview==
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| - | Antibiotic resistance mediated by constantly evolving beta-lactamases is a serious threat to human health. The mechanism of inhibition of these enzymes by therapeutic beta-lactamase inhibitors is probed using a novel approach involving Raman microscopy and x-ray crystallography. We have presented here the high resolution crystal structures of the beta-lactamase inhibitors sulbactam and clavulanic acid bound to the deacylation-deficient E166A variant of SHV-1 beta-lactamase. Our previous Raman measurements have identified the trans-enamine species for both inhibitors and were used to guide the soaking time and concentration to achieve full occupancy of the active sites. The two inhibitor-bound x-ray structures revealed a linear trans-enamine intermediate covalently attached to the active site Ser-70 residue. This intermediate was thought to play a key role in the transient inhibition of class A beta-lactamases. Both the Raman and x-ray data indicated that the clavulanic acid intermediate is decarboxylated. When compared with our previously determined tazobactam-bound inhibitor structure, our new inhibitor-bound structures revealed an increased disorder in the tail region of the inhibitors as well as in the enamine skeleton. The x-ray crystallographic observations correlated with the broadening of the O-C=C-N (enamine) symmetric stretch Raman band near 1595 cm(-1). Band broadening in the sulbactam and clavulanic acid inter-mediates reflected a heterogeneous conformational population that results from variations of torsional angles in the O-(C=O)-C=C=NH-C skeleton. These observations led us to conclude that the conformational stability of the trans-enamine form is critical for their transient inhibitory efficacy.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_16055923}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16055923 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_16055923}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Inhibitor design]] | | [[Category: Inhibitor design]] |
| | [[Category: Penicillinase]] | | [[Category: Penicillinase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 18:34:58 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:28:19 2008'' |
Revision as of 08:28, 28 July 2008
Template:STRUCTURE 2a49
Crystal structure of clavulanic acid bound to E166A variant of SHV-1 beta-lactamase
Template:ABSTRACT PUBMED 16055923
About this Structure
2A49 is a Single protein structure of sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA.
Reference
High resolution crystal structures of the trans-enamine intermediates formed by sulbactam and clavulanic acid and E166A SHV-1 {beta}-lactamase., Padayatti PS, Helfand MS, Totir MA, Carey MP, Carey PR, Bonomo RA, van den Akker F, J Biol Chem. 2005 Oct 14;280(41):34900-7. Epub 2005 Jul 29. PMID:16055923
Page seeded by OCA on Mon Jul 28 11:28:19 2008
