2hfj: Difference between revisions
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== | ==Pikromycin thioesterase with covalent pentaketide affinity label== | ||
<StructureSection load='2hfj' size='340' side='right'caption='[[2hfj]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2hfj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_venezuelae Streptomyces venezuelae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HFJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HFJ 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]] 1.95Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YML:[(3R,4S,5S,7R)-4,8-DIHYDROXY-3,5,7-TRIMETHYL-2-OXOOCTYL]PHOSPHONIC+ACID'>YML</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=2hfj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hfj OCA], [https://pdbe.org/2hfj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hfj RCSB], [https://www.ebi.ac.uk/pdbsum/2hfj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hfj ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PIKA4_STRVZ PIKA4_STRVZ] Involved in the biosynthesis of 12- and 14-membered ring macrolactone antibiotics such as methymycin and neomethymycin, and pikromycin and narbomycin, respectively. Component of the pikromycin PKS which catalyzes the biosynthesis of both precursors 10-deoxymethynolide (12-membered ring macrolactone) and narbonolide (14-membered ring macrolactone). Chain elongation through PikAI, PikAII and PikAIII followed by thioesterase catalyzed termination results in the production of 10-deoxymethynolide, while continued elongation through PikAIV, followed by thioesterase (TE) catalyzed cyclization results in the biosynthesis of the narbonolide. The thioesterase can use a series of diketide-N-acetylcysteamine (SNAC) thioesters, but has a strong preference for the 2-methyl-3-ketopentanoyl-SNAC over the stereoisomers of 2-methyl-3-hydroxyacyl-SNAC (PubMed:12379101, PubMed:12733905).<ref>PMID:10421766</ref> <ref>PMID:10676969</ref> <ref>PMID:12379101</ref> <ref>PMID:12733905</ref> <ref>PMID:16969372</ref> <ref>PMID:17719493</ref> <ref>PMID:19027305</ref> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hf/2hfj_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2hfj ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Polyketides are a class of biologically active microbial and plant-derived metabolites that possess a high degree of structural and functional diversity and include many human therapeutics, among them anti-infective and anti-cancer drugs, growth promoters and anti-parasitic agents. The macrolide antibiotics, characterized by a glycoside-linked macrolactone, constitute an important class of polyketides, including erythromycin and the natural ketolide anti-infective agent pikromycin. Here we describe new mechanistic details of macrolactone ring formation catalyzed by the pikromycin polyketide synthase thioesterase domain from Streptomyces venezuelae. A pentaketide phosphonate mimic of the final pikromycin linear chain-elongation intermediate was synthesized and shown to be an active site affinity label. The crystal structures of the affinity-labeled enzyme and of a 12-membered-ring macrolactone product complex suggest a mechanism for cyclization in which a hydrophilic barrier in the enzyme and structural restraints of the substrate induce a curled conformation to direct macrolactone ring formation. | Polyketides are a class of biologically active microbial and plant-derived metabolites that possess a high degree of structural and functional diversity and include many human therapeutics, among them anti-infective and anti-cancer drugs, growth promoters and anti-parasitic agents. The macrolide antibiotics, characterized by a glycoside-linked macrolactone, constitute an important class of polyketides, including erythromycin and the natural ketolide anti-infective agent pikromycin. Here we describe new mechanistic details of macrolactone ring formation catalyzed by the pikromycin polyketide synthase thioesterase domain from Streptomyces venezuelae. A pentaketide phosphonate mimic of the final pikromycin linear chain-elongation intermediate was synthesized and shown to be an active site affinity label. The crystal structures of the affinity-labeled enzyme and of a 12-membered-ring macrolactone product complex suggest a mechanism for cyclization in which a hydrophilic barrier in the enzyme and structural restraints of the substrate induce a curled conformation to direct macrolactone ring formation. | ||
Structural basis for macrolactonization by the pikromycin thioesterase.,Akey DL, Kittendorf JD, Giraldes JW, Fecik RA, Sherman DH, Smith JL Nat Chem Biol. 2006 Oct;2(10):537-42. Epub 2006 Sep 10. PMID:16969372<ref>PMID:16969372</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 2hfj" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Streptomyces venezuelae]] | [[Category: Streptomyces venezuelae]] | ||
[[Category: Akey | [[Category: Akey DL]] | ||
[[Category: Fecik | [[Category: Fecik RA]] | ||
[[Category: Giraldes | [[Category: Giraldes JW]] | ||
[[Category: Kittendorf | [[Category: Kittendorf JD]] | ||
[[Category: Sherman | [[Category: Sherman DH]] | ||
[[Category: Smith | [[Category: Smith JL]] | ||
