4lcm: Difference between revisions
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==Simvastatin Synthase (LOVD), from Aspergillus Terreus, LovD9 mutant (simh9014)== | |||
<StructureSection load='4lcm' size='340' side='right' caption='[[4lcm]], [[Resolution|resolution]] 3.19Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4lcm]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspte Aspte]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LCM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LCM FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hl9|3hl9]], [[3hlb|3hlb]], [[3hlc|3hlc]], [[3hld|3hld]], [[3hle|3hle]], [[3hlf|3hlf]], [[3hlg|3hlg]], [[4lcl|4lcl]]</td></tr> | |||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lovD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=33178 ASPTE])</td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lcm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lcm RCSB], [http://www.ebi.ac.uk/pdbsum/4lcm PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Natural enzymes have evolved to perform their cellular functions under complex selective pressures, which often require their catalytic activities to be regulated by other proteins. We contrasted a natural enzyme, LovD, which acts on a protein-bound (LovF) acyl substrate, with a laboratory-generated variant that was transformed by directed evolution to accept instead a small free acyl thioester and no longer requires the acyl carrier protein. The resulting 29-mutant variant is 1,000-fold more efficient in the synthesis of the drug simvastatin than the wild-type LovD. This is to our knowledge the first nonpatent report of the enzyme currently used for the manufacture of simvastatin as well as the intermediate evolved variants. Crystal structures and microsecond-scale molecular dynamics simulations revealed the mechanism by which the laboratory-generated mutations free LovD from dependence on protein-protein interactions. Mutations markedly altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF. | |||
The role of distant mutations and allosteric regulation on LovD active site dynamics.,Jimenez-Oses G, Osuna S, Gao X, Sawaya MR, Gilson L, Collier SJ, Huisman GW, Yeates TO, Tang Y, Houk KN Nat Chem Biol. 2014 Jun;10(6):431-6. doi: 10.1038/nchembio.1503. Epub 2014 Apr, 13. PMID:24727900<ref>PMID:24727900</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Aspte]] | [[Category: Aspte]] | ||
[[Category: Gao, X.]] | [[Category: Gao, X.]] | ||
Revision as of 10:18, 28 May 2014
Simvastatin Synthase (LOVD), from Aspergillus Terreus, LovD9 mutant (simh9014)Simvastatin Synthase (LOVD), from Aspergillus Terreus, LovD9 mutant (simh9014)
Structural highlights
Publication Abstract from PubMedNatural enzymes have evolved to perform their cellular functions under complex selective pressures, which often require their catalytic activities to be regulated by other proteins. We contrasted a natural enzyme, LovD, which acts on a protein-bound (LovF) acyl substrate, with a laboratory-generated variant that was transformed by directed evolution to accept instead a small free acyl thioester and no longer requires the acyl carrier protein. The resulting 29-mutant variant is 1,000-fold more efficient in the synthesis of the drug simvastatin than the wild-type LovD. This is to our knowledge the first nonpatent report of the enzyme currently used for the manufacture of simvastatin as well as the intermediate evolved variants. Crystal structures and microsecond-scale molecular dynamics simulations revealed the mechanism by which the laboratory-generated mutations free LovD from dependence on protein-protein interactions. Mutations markedly altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF. The role of distant mutations and allosteric regulation on LovD active site dynamics.,Jimenez-Oses G, Osuna S, Gao X, Sawaya MR, Gilson L, Collier SJ, Huisman GW, Yeates TO, Tang Y, Houk KN Nat Chem Biol. 2014 Jun;10(6):431-6. doi: 10.1038/nchembio.1503. Epub 2014 Apr, 13. PMID:24727900[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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