2a49: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2a49.gif|left|200px]] | [[Image:2a49.gif|left|200px]] | ||
<!-- | |||
The line below this paragraph, containing "STRUCTURE_2a49", creates the "Structure Box" on the page. | |||
You may change the PDB parameter (which sets the PDB file loaded into the applet) | |||
or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | |||
or leave the SCENE parameter empty for the default display. | |||
| | --> | ||
| | {{STRUCTURE_2a49| PDB=2a49 | SCENE= }} | ||
}} | |||
'''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''' | ||
| Line 33: | Line 30: | ||
[[Category: Padayatti, P S.]] | [[Category: Padayatti, P S.]] | ||
[[Category: Totir, M A.]] | [[Category: Totir, M A.]] | ||
[[Category: | [[Category: Beta-lactam hydrolase]] | ||
[[Category: | [[Category: Beta-lactamase]] | ||
[[Category: | [[Category: Covalent intermediate]] | ||
[[Category: | [[Category: Detergent binding]] | ||
[[Category: | [[Category: Inhibitor design]] | ||
[[Category: | [[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 | |||
Revision as of 18:34, 3 May 2008
Crystal structure of clavulanic acid bound to E166A variant of SHV-1 beta-lactamase
OverviewOverview
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.
About this StructureAbout this Structure
2A49 is a Single protein structure of sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA.
ReferenceReference
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 Sat May 3 18:34:58 2008