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< | ==Serum paraoxonase-1 by directed evolution at pH 6.5 in complex with 2-hydroxyquinoline== | ||
<StructureSection load='3srg' size='340' side='right'caption='[[3srg]], [[Resolution|resolution]] 2.19Å' scene=''> | |||
== Structural highlights == | |||
or the | <table><tr><td colspan='2'>[[3srg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SRG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SRG FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.19Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=OCH:QUINOLIN-2(1H)-ONE'>OCH</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3srg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3srg OCA], [https://pdbe.org/3srg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3srg RCSB], [https://www.ebi.ac.uk/pdbsum/3srg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3srg ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The origins of enzyme specificity are well established. However, the molecular details underlying the ability of a single active site to promiscuously bind different substrates and catalyze different reactions remain largely unknown. To better understand the molecular basis of enzyme promiscuity, we studied the mammalian serum paraoxonase 1 (PON1) whose native substrates are lipophilic lactones. We describe the crystal structures of PON1 at a catalytically relevant pH and of its complex with a lactone analogue. The various PON1 structures and the analysis of active-site mutants guided the generation of docking models of the various substrates and their reaction intermediates. The models suggest that promiscuity is driven by coincidental overlaps between the reactive intermediate for the native lactonase reaction and the ground and/or intermediate states of the promiscuous reactions. This overlap is also enabled by different active-site conformations: the lactonase activity utilizes one active-site conformation whereas the promiscuous phosphotriesterase activity utilizes another. The hydrolysis of phosphotriesters, and of the aromatic lactone dihydrocoumarin, is also driven by an alternative catalytic mode that uses only a subset of the active-site residues utilized for lactone hydrolysis. Indeed, PON1's active site shows a remarkable level of networking and versatility whereby multiple residues share the same task and individual active-site residues perform multiple tasks (e.g., binding the catalytic calcium and activating the hydrolytic water). Overall, the coexistence of multiple conformations and alternative catalytic modes within the same active site underlines PON1's promiscuity and evolutionary potential. | |||
Catalytic Versatility and Backups in Enzyme Active Sites: The Case of Serum Paraoxonase 1.,Ben-David M, Elias M, Filippi JJ, Dunach E, Silman I, Sussman JL, Tawfik DS J Mol Biol. 2012 Mar 1. PMID:22387469<ref>PMID:22387469</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3srg" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Serum Paraoxonase|Serum Paraoxonase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[ | |||
== | |||
< | |||
[[Category: | |||
[[Category: Synthetic construct]] | [[Category: Synthetic construct]] | ||
[[Category: David | [[Category: Ben David M]] | ||
[[Category: Elias | [[Category: Elias M]] | ||
[[Category: Silman | [[Category: Silman I]] | ||
[[Category: Sussman | [[Category: Sussman JL]] | ||
[[Category: Tawfik | [[Category: Tawfik DS]] | ||
Latest revision as of 12:41, 30 October 2024
Serum paraoxonase-1 by directed evolution at pH 6.5 in complex with 2-hydroxyquinolineSerum paraoxonase-1 by directed evolution at pH 6.5 in complex with 2-hydroxyquinoline
Structural highlights
Publication Abstract from PubMedThe origins of enzyme specificity are well established. However, the molecular details underlying the ability of a single active site to promiscuously bind different substrates and catalyze different reactions remain largely unknown. To better understand the molecular basis of enzyme promiscuity, we studied the mammalian serum paraoxonase 1 (PON1) whose native substrates are lipophilic lactones. We describe the crystal structures of PON1 at a catalytically relevant pH and of its complex with a lactone analogue. The various PON1 structures and the analysis of active-site mutants guided the generation of docking models of the various substrates and their reaction intermediates. The models suggest that promiscuity is driven by coincidental overlaps between the reactive intermediate for the native lactonase reaction and the ground and/or intermediate states of the promiscuous reactions. This overlap is also enabled by different active-site conformations: the lactonase activity utilizes one active-site conformation whereas the promiscuous phosphotriesterase activity utilizes another. The hydrolysis of phosphotriesters, and of the aromatic lactone dihydrocoumarin, is also driven by an alternative catalytic mode that uses only a subset of the active-site residues utilized for lactone hydrolysis. Indeed, PON1's active site shows a remarkable level of networking and versatility whereby multiple residues share the same task and individual active-site residues perform multiple tasks (e.g., binding the catalytic calcium and activating the hydrolytic water). Overall, the coexistence of multiple conformations and alternative catalytic modes within the same active site underlines PON1's promiscuity and evolutionary potential. Catalytic Versatility and Backups in Enzyme Active Sites: The Case of Serum Paraoxonase 1.,Ben-David M, Elias M, Filippi JJ, Dunach E, Silman I, Sussman JL, Tawfik DS J Mol Biol. 2012 Mar 1. PMID:22387469[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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