1jwp
From Proteopedia
(New page: 200px<br /><applet load="1jwp" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jwp, resolution 1.75Å" /> '''Structure of M182T m...) |
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| - | [[Image:1jwp.jpg|left|200px]]<br /><applet load="1jwp" size=" | + | [[Image:1jwp.jpg|left|200px]]<br /><applet load="1jwp" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1jwp, resolution 1.75Å" /> | caption="1jwp, resolution 1.75Å" /> | ||
'''Structure of M182T mutant of TEM-1 beta-lactamase'''<br /> | '''Structure of M182T mutant of TEM-1 beta-lactamase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Pressured by antibiotic use, resistance enzymes have been evolving new | + | Pressured by antibiotic use, resistance enzymes have been evolving new activities. Does such evolution have a cost? To investigate this question at the molecular level, clinically isolated mutants of the beta-lactamase TEM-1 were studied. When purified, mutant enzymes had increased activity against cephalosporin antibiotics but lost both thermodynamic stability and kinetic activity against their ancestral targets, penicillins. The X-ray crystallographic structures of three mutant enzymes were determined. These structures suggest that activity gain and stability loss is related to an enlarged active site cavity in the mutant enzymes. In several clinically isolated mutant enzymes, a secondary substitution is observed far from the active site (Met182-->Thr). This substitution had little effect on enzyme activity but restored stability lost by substitutions near the active site. This regained stability conferred an advantage in vivo. This pattern of stability loss and restoration may be common in the evolution of new enzyme activity. |
==About this Structure== | ==About this Structure== | ||
| - | 1JWP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with PO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http:// | + | 1JWP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=PO4:'>PO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JWP OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Minasov, G.]] | [[Category: Minasov, G.]] | ||
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: Wang, X.]] | [[Category: Wang, X.]] | ||
[[Category: PO4]] | [[Category: PO4]] | ||
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[[Category: tem-1]] | [[Category: tem-1]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:27:36 2008'' |
Revision as of 11:27, 21 February 2008
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Structure of M182T mutant of TEM-1 beta-lactamase
Overview
Pressured by antibiotic use, resistance enzymes have been evolving new activities. Does such evolution have a cost? To investigate this question at the molecular level, clinically isolated mutants of the beta-lactamase TEM-1 were studied. When purified, mutant enzymes had increased activity against cephalosporin antibiotics but lost both thermodynamic stability and kinetic activity against their ancestral targets, penicillins. The X-ray crystallographic structures of three mutant enzymes were determined. These structures suggest that activity gain and stability loss is related to an enlarged active site cavity in the mutant enzymes. In several clinically isolated mutant enzymes, a secondary substitution is observed far from the active site (Met182-->Thr). This substitution had little effect on enzyme activity but restored stability lost by substitutions near the active site. This regained stability conferred an advantage in vivo. This pattern of stability loss and restoration may be common in the evolution of new enzyme activity.
About this Structure
1JWP is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs., Wang X, Minasov G, Shoichet BK, J Mol Biol. 2002 Jun 28;320(1):85-95. PMID:12079336
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