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[[Image:2cib.jpg|left|200px]]
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{{STRUCTURE_2cib|  PDB=2cib  |  SCENE=  }}
'''HIGH THROUGHPUT SCREENING AND X-RAY CRYSTALLOGRAPHY ASSISTED EVALUATION OF SMALL MOLECULE SCAFFOLDS FOR CYP51 INHIBITORS'''


==High throughput screening and x-ray crystallography assisted evaluation of small molecule scaffolds for CYP51 inhibitors==
<StructureSection load='2cib' size='340' side='right'caption='[[2cib]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2cib]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CIB 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]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CM6:(2S)-2-[(2,1,3-BENZOTHIADIAZOL-4-YLSULFONYL)AMINO]-2-PHENYL-N-PYRIDIN-4-YLACETAMIDE'>CM6</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=2cib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cib OCA], [https://pdbe.org/2cib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cib RCSB], [https://www.ebi.ac.uk/pdbsum/2cib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cib ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CP51_MYCTU CP51_MYCTU] Its precise biological substrate is not known. Catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.<ref>PMID:9756611</ref> <ref>PMID:10430874</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/ci/2cib_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=2cib ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Sterol 14alpha-demethylase (CYP51), a major checkpoint in membrane sterol biosynthesis, is a key target for fungal antibiotic therapy. We sought small organic molecules for lead candidate CYP51 inhibitors. The changes in CYP51 spectral properties following ligand binding make CYP51 a convenient target for high-throughput screening technologies. These changes are characteristic of either substrate binding (type I) or inhibitor binding (type II) in the active site. We screened a library of 20,000 organic molecules against Mycobacterium tuberculosis CYP51 (CYP51(Mt)), examined the top type I and type II binding hits for their inhibitory effects on M. tuberculosis in broth culture, and analyzed them spectrally for their ability to discriminate between CYP51(Mt) and two reference M. tuberculosis CYP proteins, CYP130 and CYP125. We determined the binding mode for one of the top type II hits, alpha-ethyl-N-4-pyridinyl-benzeneacetamide (EPBA), by solving the X-ray structure of the CYP51(Mt)-EPBA complex to a resolution of 1.53 A. EPBA binds coordinately to the heme iron in the CYP51(Mt) active site through a lone pair of nitrogen electrons and also through hydrogen bonds with residues H259 and Y76, which are invariable in the CYP51 family, and hydrophobic interactions in a phylum- and/or substrate-specific cavity of CYP51. We also identified a second compound with structural and binding properties similar to those of EPBA, 2-(benzo[d]-2,1,3-thiadiazole-4-sulfonyl)-2-amino-2-phenyl-N-(pyridinyl-4) -acetamide (BSPPA). The congruence between the geometries of EPBA and BSPPA and the CYP51 binding site singles out EPBA and BSPPA as lead candidate CYP51 inhibitors with optimization potential for efficient discrimination between host and pathogen enzymes.


==Overview==
Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography.,Podust LM, von Kries JP, Eddine AN, Kim Y, Yermalitskaya LV, Kuehne R, Ouellet H, Warrier T, Altekoster M, Lee JS, Rademann J, Oschkinat H, Kaufmann SH, Waterman MR Antimicrob Agents Chemother. 2007 Nov;51(11):3915-23. Epub 2007 Sep 10. PMID:17846131<ref>PMID:17846131</ref>
Sterol 14alpha-demethylase (CYP51), a major checkpoint in membrane sterol biosynthesis, is a key target for fungal antibiotic therapy. We sought small organic molecules for lead candidate CYP51 inhibitors. The changes in CYP51 spectral properties following ligand binding make CYP51 a convenient target for high-throughput screening technologies. These changes are characteristic of either substrate binding (type I) or inhibitor binding (type II) in the active site. We screened a library of 20,000 organic molecules against Mycobacterium tuberculosis CYP51 (CYP51(Mt)), examined the top type I and type II binding hits for their inhibitory effects on M. tuberculosis in broth culture, and analyzed them spectrally for their ability to discriminate between CYP51(Mt) and two reference M. tuberculosis CYP proteins, CYP130 and CYP125. We determined the binding mode for one of the top type II hits, alpha-ethyl-N-4-pyridinyl-benzeneacetamide (EPBA), by solving the X-ray structure of the CYP51(Mt)-EPBA complex to a resolution of 1.53 A. EPBA binds coordinately to the heme iron in the CYP51(Mt) active site through a lone pair of nitrogen electrons and also through hydrogen bonds with residues H259 and Y76, which are invariable in the CYP51 family, and hydrophobic interactions in a phylum- and/or substrate-specific cavity of CYP51. We also identified a second compound with structural and binding properties similar to those of EPBA, 2-(benzo[d]-2,1,3-thiadiazole-4-sulfonyl)-2-amino-2-phenyl-N-(pyridinyl-4) -acetamide (BSPPA). The congruence between the geometries of EPBA and BSPPA and the CYP51 binding site singles out EPBA and BSPPA as lead candidate CYP51 inhibitors with optimization potential for efficient discrimination between host and pathogen enzymes.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2CIB is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CIB OCA].
</div>
<div class="pdbe-citations 2cib" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography., Podust LM, von Kries JP, Eddine AN, Kim Y, Yermalitskaya LV, Kuehne R, Ouellet H, Warrier T, Altekoster M, Lee JS, Rademann J, Oschkinat H, Kaufmann SH, Waterman MR, Antimicrob Agents Chemother. 2007 Nov;51(11):3915-23. Epub 2007 Sep 10. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17846131 17846131]
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
[[Category: Mycobacterium tuberculosis]]
== References ==
[[Category: Single protein]]
<references/>
[[Category: Sterol 14-demethylase]]
__TOC__
[[Category: Kim, Y.]]
</StructureSection>
[[Category: Kries, J P.Von.]]
[[Category: Large Structures]]
[[Category: Podust, L M.]]
[[Category: Mycobacterium tuberculosis H37Rv]]
[[Category: Waterman, M R.]]
[[Category: Kim Y]]
[[Category: Yermalitskaya, L V.]]
[[Category: Podust LM]]
[[Category: Heme]]
[[Category: Von Kries JP]]
[[Category: Heme lipid synthesis]]
[[Category: Waterman MR]]
[[Category: Metal-binding]]
[[Category: Yermalitskaya LV]]
[[Category: Monooxygenase]]
[[Category: Nadp]]
[[Category: Oxidoreductase]]
[[Category: Protein-inhibitor complex]]
[[Category: Steroid biosynthesis]]
[[Category: Sterol biosynthesis]]
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