1ia3
From Proteopedia
(New page: 200px<br /><applet load="1ia3" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ia3, resolution 1.78Å" /> '''Candida albicans dih...) |
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| - | [[Image:1ia3.gif|left|200px]]<br /><applet load="1ia3" size=" | + | [[Image:1ia3.gif|left|200px]]<br /><applet load="1ia3" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1ia3, resolution 1.78Å" /> | caption="1ia3, resolution 1.78Å" /> | ||
'''Candida albicans dihydrofolate reductase complex in which the dihydronicotinamide moiety of dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) is displaced by 5-[(4-TERT-BUTYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW995)'''<br /> | '''Candida albicans dihydrofolate reductase complex in which the dihydronicotinamide moiety of dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) is displaced by 5-[(4-TERT-BUTYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW995)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | X-ray crystallographic analysis of 5-(4'-substituted | + | X-ray crystallographic analysis of 5-(4'-substituted phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two distinct modes of binding. The two compounds with small 4'-substituents (H and CH3) were found to bind with the phenyl group oriented in the plane of the quinazoline ring system and positioned adjacent to the C-helix. In contrast, the more selective inhibitors with larger 4'-substituents (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl group perpendicular to the quinazoline ring and positioned in the region of the active site that typically binds the dihydronicotinamide moiety of NADPH. The cofactor appeared bound to DHFR but with the disordered dihydronicotinamide swung away from the protein surface and into solution. This unusual inhibitor binding mode may play an important role in the high DHFR selectivity of these compounds and also may provide new ideas for inhibitor design. |
==About this Structure== | ==About this Structure== | ||
| - | 1IA3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Candida_albicans Candida albicans] with NDP, TQ5 and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Full crystallographic information is available from [http:// | + | 1IA3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Candida_albicans Candida albicans] with <scene name='pdbligand=NDP:'>NDP</scene>, <scene name='pdbligand=TQ5:'>TQ5</scene> and <scene name='pdbligand=MES:'>MES</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IA3 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Howard, A | + | [[Category: Howard, A J.]] |
| - | [[Category: Kuyper, L | + | [[Category: Kuyper, L F.]] |
[[Category: Whitlow, M.]] | [[Category: Whitlow, M.]] | ||
[[Category: MES]] | [[Category: MES]] | ||
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[[Category: reductase]] | [[Category: reductase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:09:42 2008'' |
Revision as of 11:09, 21 February 2008
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Candida albicans dihydrofolate reductase complex in which the dihydronicotinamide moiety of dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) is displaced by 5-[(4-TERT-BUTYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW995)
Overview
X-ray crystallographic analysis of 5-(4'-substituted phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two distinct modes of binding. The two compounds with small 4'-substituents (H and CH3) were found to bind with the phenyl group oriented in the plane of the quinazoline ring system and positioned adjacent to the C-helix. In contrast, the more selective inhibitors with larger 4'-substituents (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl group perpendicular to the quinazoline ring and positioned in the region of the active site that typically binds the dihydronicotinamide moiety of NADPH. The cofactor appeared bound to DHFR but with the disordered dihydronicotinamide swung away from the protein surface and into solution. This unusual inhibitor binding mode may play an important role in the high DHFR selectivity of these compounds and also may provide new ideas for inhibitor design.
About this Structure
1IA3 is a Single protein structure of sequence from Candida albicans with , and as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
Reference
X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor., Whitlow M, Howard AJ, Stewart D, Hardman KD, Chan JH, Baccanari DP, Tansik RL, Hong JS, Kuyper LF, J Med Chem. 2001 Aug 30;44(18):2928-32. PMID:11520201
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