2ci0: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
(12 intermediate revisions by the same user not shown)
Line 1: Line 1:
{{Seed}}
[[Image:2ci0.png|left|200px]]


<!--
==High throughput screening and x-ray crystallography assisted evaluation of small molecule scaffolds for CYP51 inhibitors==
The line below this paragraph, containing "STRUCTURE_2ci0", creates the "Structure Box" on the page.
<StructureSection load='2ci0' size='340' side='right'caption='[[2ci0]], [[Resolution|resolution]] 1.53&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2ci0]] 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=2CI0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CI0 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.53&#8491;</td></tr>
-->
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1CM:(2R)-2-PHENYL-N-PYRIDIN-4-YLBUTANAMIDE'>1CM</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
{{STRUCTURE_2ci0|  PDB=2ci0  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ci0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ci0 OCA], [https://pdbe.org/2ci0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ci0 RCSB], [https://www.ebi.ac.uk/pdbsum/2ci0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ci0 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/2ci0_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=2ci0 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.


===HIGH THROUGHPUT SCREENING AND X-RAY CRYSTALLOGRAPHY ASSISTED EVALUATION OF SMALL MOLECULE SCAFFOLDS FOR CYP51 INHIBITORS===
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>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2ci0" style="background-color:#fffaf0;"></div>


<!--
==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_17846131}}, adds the Publication Abstract to the page
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 17846131 is the PubMed ID number.
== References ==
-->
<references/>
{{ABSTRACT_PUBMED_17846131}}
__TOC__
 
</StructureSection>
==About this Structure==
[[Category: Large Structures]]
2CI0 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=2CI0 OCA].
[[Category: Mycobacterium tuberculosis H37Rv]]
 
[[Category: Kim Y]]
==Reference==
[[Category: Podust LM]]
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]
[[Category: Von Kries JP]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Waterman MR]]
[[Category: Single protein]]
[[Category: Yermalitskaya LV]]
[[Category: Sterol 14-demethylase]]
[[Category: Kim, Y.]]
[[Category: Kries, J P.Von.]]
[[Category: Podust, L M.]]
[[Category: Waterman, M R.]]
[[Category: Yermalitskaya, L V.]]
[[Category: Heme]]
[[Category: Heme lipid synthesis]]
[[Category: Metal-binding]]
[[Category: Monooxygenase]]
[[Category: Nadp]]
[[Category: Oxidoreductase]]
[[Category: Protein-inhibitor complex]]
[[Category: Steroid biosynthesis]]
[[Category: Sterol biosynthesis]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:02:54 2008''

Latest revision as of 17:17, 13 December 2023

High throughput screening and x-ray crystallography assisted evaluation of small molecule scaffolds for CYP51 inhibitorsHigh throughput screening and x-ray crystallography assisted evaluation of small molecule scaffolds for CYP51 inhibitors

Structural highlights

2ci0 is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.53Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

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.

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[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Aoyama Y, Horiuchi T, Gotoh O, Noshiro M, Yoshida Y. CYP51-like gene of Mycobacterium tuberculosis actually encodes a P450 similar to eukaryotic CYP51. J Biochem. 1998 Oct;124(4):694-6. PMID:9756611
  2. ↑ Bellamine A, Mangla AT, Nes WD, Waterman MR. Characterization and catalytic properties of the sterol 14alpha-demethylase from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8937-42. PMID:10430874
  3. ↑ 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. Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography. Antimicrob Agents Chemother. 2007 Nov;51(11):3915-23. Epub 2007 Sep 10. PMID:17846131 doi:10.1128/AAC.00311-07

2ci0, resolution 1.53Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=2ci0&oldid=3985071"