4bmk: Difference between revisions
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==Serine Palmitoyltransferase K265A from S. paucimobilis with bound PLP- Myriocin Aldimine== | |||
<StructureSection load='4bmk' size='340' side='right' caption='[[4bmk]], [[Resolution|resolution]] 1.62Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bmk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Sphingomonas_paucimobilis Sphingomonas paucimobilis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BMK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BMK FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MYB:DECARBOXYLATED+MYRIOCIN'>MYB</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Serine_C-palmitoyltransferase Serine C-palmitoyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.50 2.3.1.50] </span></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=4bmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bmk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bmk RCSB], [http://www.ebi.ac.uk/pdbsum/4bmk PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Sphingolipids (SLs) are essential components of cellular membranes formed from the condensation of L-serine and a long-chain acyl thioester. This first step is catalysed by the pyridoxal 5-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) which is a promising therapeutic target. The fungal natural product myriocin is a potent inhibitor of SPT and is widely-used to block SL biosynthesis despite a lack of a detailed understanding of its molecular mechanism. By combining spectroscopy, mass spectrometry, x-ray crystallography and kinetics we have characterised the molecular details of SPT inhibition by myriocin. Myriocin initially forms an external aldimine with PLP at the active site and a structure of the resulting co-complex explains its nanomolar affinity for the enzyme. This co-complex then catalytically degrades via an unexpected 'retro-aldol like' cleavage mechanism to a C18 aldehyde which in turn acts as a suicide inhibitor of SPT by covalent modification of the essential catalytic lysine. This surprising dual mechanism of inhibition rationalises the extraordinary potency and longevity of myriocin inhibition. | |||
The chemical basis of serine palmitoyltransferase inhibition by myriocin.,Wadsworth JM, Clarke DJ, McMahon SA, Lowther JP, Beattie AE, Langridge-Smith PR, Broughton HB, Dunn TM, Naismith JH, Campopiano DJ J Am Chem Soc. 2013 Aug 19. PMID:23957439<ref>PMID:23957439</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
==See Also== | |||
*[[Serine palmitoyltransferase|Serine palmitoyltransferase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Serine C-palmitoyltransferase]] | [[Category: Serine C-palmitoyltransferase]] | ||
[[Category: Sphingomonas paucimobilis]] | [[Category: Sphingomonas paucimobilis]] | ||
[[Category: Beattie, A E | [[Category: Beattie, A E]] | ||
[[Category: Campopiano, D J | [[Category: Campopiano, D J]] | ||
[[Category: Clarke, D J | [[Category: Clarke, D J]] | ||
[[Category: Dunn, T M | [[Category: Dunn, T M]] | ||
[[Category: Lowther, J | [[Category: Lowther, J]] | ||
[[Category: McMahon, S A | [[Category: McMahon, S A]] | ||
[[Category: Naismith, J H | [[Category: Naismith, J H]] | ||
[[Category: Wadsworth, J M | [[Category: Wadsworth, J M]] | ||
[[Category: Antibiotic isp-1]] | [[Category: Antibiotic isp-1]] | ||
[[Category: External aldimine]] | [[Category: External aldimine]] | ||
Revision as of 09:59, 21 December 2014
Serine Palmitoyltransferase K265A from S. paucimobilis with bound PLP- Myriocin Aldimine
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