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< | ==Crystal structure of the C(30) carotenoid dehydrosqualene synthase from S. aureus complexed with Presqualene diphosphate (PSPP)== | ||
<StructureSection load='3npr' size='340' side='right'caption='[[3npr]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3npr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_A017934/97 Staphylococcus aureus subsp. aureus A017934/97]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NPR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NPR 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]] 2Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PS7:{(1R,2R,3R)-2-[(3E)-4,8-DIMETHYLNONA-3,7-DIEN-1-YL]-2-METHYL-3-[(1E,5E)-2,6,10-TRIMETHYLUNDECA-1,5,9-TRIEN-1-YL]CYCLOPROPYL}METHYL+TRIHYDROGEN+DIPHOSPHATE'>PS7</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=3npr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3npr OCA], [https://pdbe.org/3npr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3npr RCSB], [https://www.ebi.ac.uk/pdbsum/3npr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3npr ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CRTM_STAAU CRTM_STAAU] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
"Head-to-head" terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. Here, we report the structures of Staphylococcus aureus dehydrosqualene synthase (CrtM) complexed with its reaction intermediate, presqualene diphosphate (PSPP), the dehydrosqualene (DHS) product, as well as a series of inhibitors. The results indicate that, on initial diphosphate loss, the primary carbocation so formed bends down into the interior of the protein to react with C2,3 double bond in the prenyl acceptor to form PSPP, with the lower two-thirds of both PSPP chains occupying essentially the same positions as found in the two farnesyl chains in the substrates. The second-half reaction is then initiated by the PSPP diphosphate returning back to the Mg(2+) cluster for ionization, with the resultant DHS so formed being trapped in a surface pocket. This mechanism is supported by the observation that cationic inhibitors (of interest as antiinfectives) bind with their positive charge located in the same region as the cyclopropyl carbinyl group; that S-thiolo-diphosphates only inhibit when in the allylic site; activity results on 11 mutants show that both DXXXD conserved domains are essential for PSPP ionization; and the observation that head-to-tail isoprenoid synthases as well as terpene cyclases have ionization and alkene-donor sites which spatially overlap those found in CrtM. | |||
Mechanism of action and inhibition of dehydrosqualene synthase.,Lin FY, Liu CI, Liu YL, Zhang Y, Wang K, Jeng WY, Ko TP, Cao R, Wang AH, Oldfield E Proc Natl Acad Sci U S A. 2010 Nov 23. PMID:21098670<ref>PMID:21098670</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3npr" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Squalene synthase|Squalene synthase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[ | [[Category: Staphylococcus aureus subsp. aureus A017934/97]] | ||
[[Category: Lin F-Y]] | |||
== | [[Category: Liu C-I]] | ||
< | [[Category: Liu Y-L]] | ||
[[Category: Staphylococcus aureus]] | [[Category: Oldfield E]] | ||
[[Category: Lin | [[Category: Wang K]] | ||
[[Category: Liu | [[Category: Zhang Y]] | ||
[[Category: Liu | |||
[[Category: Oldfield | |||
[[Category: Wang | |||
[[Category: Zhang | |||
Latest revision as of 12:19, 6 September 2023
Crystal structure of the C(30) carotenoid dehydrosqualene synthase from S. aureus complexed with Presqualene diphosphate (PSPP)Crystal structure of the C(30) carotenoid dehydrosqualene synthase from S. aureus complexed with Presqualene diphosphate (PSPP)
Structural highlights
FunctionPublication Abstract from PubMed"Head-to-head" terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. Here, we report the structures of Staphylococcus aureus dehydrosqualene synthase (CrtM) complexed with its reaction intermediate, presqualene diphosphate (PSPP), the dehydrosqualene (DHS) product, as well as a series of inhibitors. The results indicate that, on initial diphosphate loss, the primary carbocation so formed bends down into the interior of the protein to react with C2,3 double bond in the prenyl acceptor to form PSPP, with the lower two-thirds of both PSPP chains occupying essentially the same positions as found in the two farnesyl chains in the substrates. The second-half reaction is then initiated by the PSPP diphosphate returning back to the Mg(2+) cluster for ionization, with the resultant DHS so formed being trapped in a surface pocket. This mechanism is supported by the observation that cationic inhibitors (of interest as antiinfectives) bind with their positive charge located in the same region as the cyclopropyl carbinyl group; that S-thiolo-diphosphates only inhibit when in the allylic site; activity results on 11 mutants show that both DXXXD conserved domains are essential for PSPP ionization; and the observation that head-to-tail isoprenoid synthases as well as terpene cyclases have ionization and alkene-donor sites which spatially overlap those found in CrtM. Mechanism of action and inhibition of dehydrosqualene synthase.,Lin FY, Liu CI, Liu YL, Zhang Y, Wang K, Jeng WY, Ko TP, Cao R, Wang AH, Oldfield E Proc Natl Acad Sci U S A. 2010 Nov 23. PMID:21098670[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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