3l4d: Difference between revisions
New page: {{Seed}} left|200px <!-- The line below this paragraph, containing "STRUCTURE_3l4d", creates the "Structure Box" on the page. You may change the PDB parameter (which se... |
No edit summary |
||
| (7 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
< | ==Crystal structure of sterol 14-alpha demethylase (CYP51) from Leishmania infantum in complex with fluconazole== | ||
<StructureSection load='3l4d' size='340' side='right'caption='[[3l4d]], [[Resolution|resolution]] 2.75Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3l4d]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_infantum Leishmania infantum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3L4D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3L4D 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]] 2.75Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=N8E:3,6,9,12,15-PENTAOXATRICOSAN-1-OL'>N8E</scene>, <scene name='pdbligand=TPF:2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL'>TPF</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=3l4d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l4d OCA], [https://pdbe.org/3l4d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3l4d RCSB], [https://www.ebi.ac.uk/pdbsum/3l4d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3l4d ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A2TEF2_LEIIN A2TEF2_LEIIN] | |||
== 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/l4/3l4d_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=3l4d ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Leishmaniasis is a major health problem that affects populations of 88 countries worldwide, with no vaccine and only a few moderately effective drugs. Here we report structure/function characterization of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. The enzyme catalyzes removal of the 14alpha-methyl group from sterol precursors. The reaction is essential for membrane biogenesis and therefore has great potential to become a target for antileishmanial chemotherapy. Although L. infantum CYP51 prefers C4-monomethylated sterol substrates, C4-norlanosterol and obtusifoliol (Vmax of 10 and 8 min-1, respectively), it is also found to 14alpha-demethylate C4-dimethylated lanosterol (Vmax=0.9 min-1) and C4-desmethylated 14alpha-methylzymosterol (Vmax =1.9 min-1). Binding parameters with six sterols were tested, the Kds ranging within 0.25-1.4 muM. Thus, L. infantum CYP51 is the first example of a plant-like sterol 14alpha-demethylase, where requirements toward the composition of the C4 atom substituents are not strict, indicative of possible branching in the postsqualene portion of sterol biosynthesis in the parasite. Comparative analysis of three CYP51 substrate binding cavities (Trypanosoma (T) brucei, T. cruzi and L. infantum) suggests that substrate preferences of plant- and fungal-like protozoan CYP51s largely depend on the differences in the enzyme active site topology. These minor structural differences are also likely to underlie CYP51 catalytic rates, drug susceptibility and can be used to design potent and specific inhibitors. | |||
Substrate preferences and catalytic parameters determined by structural characteristics of Sterol 14{alpha}-demethylase (CYP51) from Leishmania infantum.,Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI J Biol Chem. 2011 May 31. PMID:21632531<ref>PMID:21632531</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3l4d" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Leishmania infantum]] | [[Category: Leishmania infantum]] | ||
[[Category: Hargrove TY]] | |||
[[Category: Hargrove | [[Category: Lepesheva GI]] | ||
[[Category: Lepesheva | [[Category: Waterman MR]] | ||
[[Category: Waterman | [[Category: Wawrzak Z]] | ||
[[Category: Wawrzak | |||
Latest revision as of 11:30, 6 September 2023
Crystal structure of sterol 14-alpha demethylase (CYP51) from Leishmania infantum in complex with fluconazoleCrystal structure of sterol 14-alpha demethylase (CYP51) from Leishmania infantum in complex with fluconazole
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedLeishmaniasis is a major health problem that affects populations of 88 countries worldwide, with no vaccine and only a few moderately effective drugs. Here we report structure/function characterization of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. The enzyme catalyzes removal of the 14alpha-methyl group from sterol precursors. The reaction is essential for membrane biogenesis and therefore has great potential to become a target for antileishmanial chemotherapy. Although L. infantum CYP51 prefers C4-monomethylated sterol substrates, C4-norlanosterol and obtusifoliol (Vmax of 10 and 8 min-1, respectively), it is also found to 14alpha-demethylate C4-dimethylated lanosterol (Vmax=0.9 min-1) and C4-desmethylated 14alpha-methylzymosterol (Vmax =1.9 min-1). Binding parameters with six sterols were tested, the Kds ranging within 0.25-1.4 muM. Thus, L. infantum CYP51 is the first example of a plant-like sterol 14alpha-demethylase, where requirements toward the composition of the C4 atom substituents are not strict, indicative of possible branching in the postsqualene portion of sterol biosynthesis in the parasite. Comparative analysis of three CYP51 substrate binding cavities (Trypanosoma (T) brucei, T. cruzi and L. infantum) suggests that substrate preferences of plant- and fungal-like protozoan CYP51s largely depend on the differences in the enzyme active site topology. These minor structural differences are also likely to underlie CYP51 catalytic rates, drug susceptibility and can be used to design potent and specific inhibitors. Substrate preferences and catalytic parameters determined by structural characteristics of Sterol 14{alpha}-demethylase (CYP51) from Leishmania infantum.,Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI J Biol Chem. 2011 May 31. PMID:21632531[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||