2bz9
From Proteopedia
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|PDB= 2bz9 |SIZE=350|CAPTION= <scene name='initialview01'>2bz9</scene>, resolution 2.21Å | |PDB= 2bz9 |SIZE=350|CAPTION= <scene name='initialview01'>2bz9</scene>, resolution 2.21Å | ||
|SITE= <scene name='pdbsite=AC1:Hem+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC2:Hem+Binding+Site+For+Chain+B'>AC2</scene> | |SITE= <scene name='pdbsite=AC1:Hem+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC2:Hem+Binding+Site+For+Chain+B'>AC2</scene> | ||
| - | |LIGAND= <scene name='pdbligand=HEM:PROTOPORPHYRIN IX CONTAINING FE'>HEM</scene> | + | |LIGAND= <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1e9x|1E9X]], [[1ea1|1EA1]], [[1h5z|1H5Z]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2bz9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bz9 OCA], [http://www.ebi.ac.uk/pdbsum/2bz9 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2bz9 RCSB]</span> | ||
}} | }} | ||
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[[Category: Waterman, M R.]] | [[Category: Waterman, M R.]] | ||
[[Category: Yermalitskaya, L V.]] | [[Category: Yermalitskaya, L V.]] | ||
| - | [[Category: HEM]] | ||
[[Category: electron transport]] | [[Category: electron transport]] | ||
[[Category: heme]] | [[Category: heme]] | ||
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[[Category: sterol 14alpha-demethylase]] | [[Category: sterol 14alpha-demethylase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:13:59 2008'' |
Revision as of 23:14, 30 March 2008
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| , resolution 2.21Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | and | ||||||
| Ligands: | |||||||
| Activity: | Sterol 14-demethylase, with EC number 1.14.13.70 | ||||||
| Related: | 1E9X, 1EA1, 1H5Z
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
LIGAND-FREE STRUCTURE OF STEROL 14ALPHA-DEMETHYLASE FROM MYCOBACTERIUM TUBERCULOSIS IN P2(1) SPACE GROUP
Overview
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
2BZ9 is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
Reference
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
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