6q7r: Difference between revisions
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The | ==Crystal structure of OE1.3 alkylated with the mechanistic inhibitor 2-bromoacetophenone== | ||
<StructureSection load='6q7r' size='340' side='right'caption='[[6q7r]], [[Resolution|resolution]] 1.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6q7r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q7R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q7R FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AC0:1-PHENYLETHANONE'>AC0</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MHS:N1-METHYLATED+HISTIDINE'>MHS</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6q7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q7r OCA], [http://pdbe.org/6q7r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q7r RCSB], [http://www.ebi.ac.uk/pdbsum/6q7r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q7r ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The combination of computational design and laboratory evolution is a powerful and potentially versatile strategy for the development of enzymes with new functions(1-4). However, the limited functionality presented by the genetic code restricts the range of catalytic mechanisms that are accessible in designed active sites. Inspired by mechanistic strategies from small-molecule organocatalysis(5), here we report the generation of a hydrolytic enzyme that uses Ndelta-methylhistidine as a non-canonical catalytic nucleophile. Histidine methylation is essential for catalytic function because it prevents the formation of unreactive acyl-enzyme intermediates, which has been a long-standing challenge when using canonical nucleophiles in enzyme design(6-10). Enzyme performance was optimized using directed evolution protocols adapted to an expanded genetic code, affording a biocatalyst capable of accelerating ester hydrolysis with greater than 9,000-fold increased efficiency over free Ndelta-methylhistidine in solution. Crystallographic snapshots along the evolutionary trajectory highlight the catalytic devices that are responsible for this increase in efficiency. Ndelta-methylhistidine can be considered to be a genetically encodable surrogate of the widely employed nucleophilic catalyst dimethylaminopyridine(11), and its use will create opportunities to design and engineer enzymes for a wealth of valuable chemical transformations. | |||
Design and evolution of an enzyme with a non-canonical organocatalytic mechanism.,Burke AJ, Lovelock SL, Frese A, Crawshaw R, Ortmayer M, Dunstan M, Levy C, Green AP Nature. 2019 May 27. pii: 10.1038/s41586-019-1262-8. doi:, 10.1038/s41586-019-1262-8. PMID:31132786<ref>PMID:31132786</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Levy, C | <div class="pdbe-citations 6q7r" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Levy, C W]] | |||
[[Category: Computationally designed enzyme]] | |||
[[Category: Hydrolase]] | |||
Revision as of 01:53, 6 June 2019
Crystal structure of OE1.3 alkylated with the mechanistic inhibitor 2-bromoacetophenoneCrystal structure of OE1.3 alkylated with the mechanistic inhibitor 2-bromoacetophenone
Structural highlights
Publication Abstract from PubMedThe combination of computational design and laboratory evolution is a powerful and potentially versatile strategy for the development of enzymes with new functions(1-4). However, the limited functionality presented by the genetic code restricts the range of catalytic mechanisms that are accessible in designed active sites. Inspired by mechanistic strategies from small-molecule organocatalysis(5), here we report the generation of a hydrolytic enzyme that uses Ndelta-methylhistidine as a non-canonical catalytic nucleophile. Histidine methylation is essential for catalytic function because it prevents the formation of unreactive acyl-enzyme intermediates, which has been a long-standing challenge when using canonical nucleophiles in enzyme design(6-10). Enzyme performance was optimized using directed evolution protocols adapted to an expanded genetic code, affording a biocatalyst capable of accelerating ester hydrolysis with greater than 9,000-fold increased efficiency over free Ndelta-methylhistidine in solution. Crystallographic snapshots along the evolutionary trajectory highlight the catalytic devices that are responsible for this increase in efficiency. Ndelta-methylhistidine can be considered to be a genetically encodable surrogate of the widely employed nucleophilic catalyst dimethylaminopyridine(11), and its use will create opportunities to design and engineer enzymes for a wealth of valuable chemical transformations. Design and evolution of an enzyme with a non-canonical organocatalytic mechanism.,Burke AJ, Lovelock SL, Frese A, Crawshaw R, Ortmayer M, Dunstan M, Levy C, Green AP Nature. 2019 May 27. pii: 10.1038/s41586-019-1262-8. doi:, 10.1038/s41586-019-1262-8. PMID:31132786[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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