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2a3u

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{{STRUCTURE_2a3u| PDB=2a3u | SCENE= }}
{{STRUCTURE_2a3u| PDB=2a3u | SCENE= }}
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'''Crystal structure of sulbactam bound to E166A variant of SHV-1 beta-lactamase'''
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===Crystal structure of sulbactam 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.
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(as it appears on PubMed at http://www.pubmed.gov), where 16055923 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16055923}}
==About this Structure==
==About this Structure==
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[[Category: Inhibitor design]]
[[Category: Inhibitor design]]
[[Category: Penicillinase]]
[[Category: Penicillinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 18:34:00 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 22:12:41 2008''

Revision as of 19:12, 28 July 2008

Image:2a3u.png

Template:STRUCTURE 2a3u

Crystal structure of sulbactam bound to E166A variant of SHV-1 beta-lactamase

Template:ABSTRACT PUBMED 16055923

About this Structure

2A3U 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

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