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【bio-news】[Faculty1000 3.0]P450 CYP21-氟康唑复合物晶

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 281, NO. 51, pp. 39437–39443, December 22, 2006
Crystal structure of the Mycobacterium tuberculosis P450 CYP121-fluconazole complex reveals new azole drug-P450 binding mode.Seward HE, Roujeinikova A, McLean KJ, Munro AW, Leys D.
Department of Biochemistry, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE6 0HQ, United Kingdom.

Azole and triazole drugs are cytochrome P450 inhibitors widely used as fungal antibiotics and possessing potent antimycobacterial activity. We present here the crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP121 in complex with the triazole drug fluconazole, revealing a new azole heme ligation mode. In contrast to other structurally characterized cytochrome P450 azole complexes, where the azole nitrogen directly coordinates the heme iron, in CYP121 fluconazole does not displace the aqua sixth heme ligand but occupies a position that allows formation of a direct hydrogen bond to the aqua sixth heme ligand. Direct ligation of fluconazole to the heme iron is observed in a minority of CYP121 molecules, albeit with severe deviations from ideal geometry due to close contacts with active site residues. Analysis of both ligand-on and -off structures reveals the relative position of active site residues derived from the I-helix is a key determinant in the relative ratio of on and off states. Regardless, both ligand-bound states lead to P450 inactivation by active site occlusion. This previously unrecognized means of P450 inactivation is consistent with spectroscopic analyses in both solution and in the crystalline form and raises important questions relating to interaction of azoles with both pathogen and human P450s. 呵呵,我自己翻译一下.

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Paul Hollenberg
The University of Michigan, United States of America
PHARMACOLOGY & DRUG DISCOVERY

New Finding
This is a particularly interesting article because it reveals a new mode for the binding of azoles to P450s, leading to inactivation of their catalytic activity. Analysis of the crystal stucture of cytochrome P450 CYP121 with the triazole drug fluconazole complexed to the active site demonstrates that the azole nitrogen does not coordinate directly to the heme iron, but occupies a position in the P450 active site such that it forms a hydrogen bond to the sixth heme ligand, water. These results illustrate the importance of active site residues in the I-helix in determining the interactions of P450 axial ligands such as fluconazole with the heme iron. They also point out that, in some cases, the inhibitory actions of azoles may be due to interactions that do not involve direct coordination to the heme iron.

Competing interests: None declared
Evaluated 12 Apr 2007 Crystal Structure of the Mycobacterium tuberculosis P450 CYP121-Fluconazole Complex Reveals New Azole Drug-P450 Binding Mode
肺结核分支杆菌P450 CYP121与氟康唑复合物的晶体结构揭示了唑类药物与P450结合的新的模式

Azole and triazole drugs are cytochrome P450 inhibitors widely used as fungal antibiotics and possessing potent antimycobacterial activity.
唑类和三氮唑类药物作为细胞色素P450抑制剂广泛被作为抗真菌药物和抗微生物药物使用。

We present here the crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP121 in complex with the triazole drug fluconazole, revealing a new azole heme ligation mode.
我们提出了肺结核分支杆菌细胞色素P450 CYP121与三氮唑类药物氟康唑的复合物的晶体结构,揭示了唑类与亚铁血红素新的结合模式。

In contrast to other structurally characterized cytochrome P450 azole complexes, where the azole nitrogen directly coordinates the heme iron, in CYP121 fluconazole does not displace the aqua sixth heme ligand but occupies a position that allows formation of a direct hydrogen bond to the aqua sixth heme ligand.
与其他的细胞色素P450唑类复合物不同,唑类的氮原子不是直接与亚铁血红素中铁离子配合的,在CYP121中,氟康唑并不是取代了六配体亚铁血红素中的水分子,而是占有一个位置,直接通过氢键与六配体亚铁血红素配体中的水结合。

Direct ligation of fluconazole to the heme iron is observed in a minority of CYP121 molecules, albeit with severe deviations from ideal geometry due to close contacts with active site residues.
氟康唑直接与亚铁血红素铁原子直接配合在少数CYP121分子中也可以观察到,由于紧密的与活性位点残基作用,严重的背离了理想的几何形状。

Analysis of both ligand-on and –off structures reveals the relative position of active site residues derived from the I-helix is a key determinant in the relative ratio of on and off states.
分析结合了配体和未结合配体的结构揭示了从I螺旋衍生出的活性位点残基的位置对结合和未结合的比例可以产生关键的影响。

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作者:admin@医学,生命科学    2010-10-26 05:11
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