کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2189573 1096216 2006 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
NADP+ Expels both the Co-factor and a Substrate Analog from the Mycobacterium tuberculosis ThyX Active Site: Opportunities for Anti-bacterial Drug Design
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
NADP+ Expels both the Co-factor and a Substrate Analog from the Mycobacterium tuberculosis ThyX Active Site: Opportunities for Anti-bacterial Drug Design
چکیده انگلیسی

The novel flavin-dependent thymidylate synthase, ThyX, is absent in humans but several pathogenic bacteria depend exclusively on ThyX activity to synthesize thymidylate. Reduction of the enzyme-bound FAD by NADPH is suggested to be the critical first step in ThyX catalysis. We soaked Mycobacterium tuberculosis ThyX-FAD-BrdUMP ternary complex crystals in a solution containing NADP+ to gain structural insights into the reductive step of the catalytic cycle. Surprisingly, the NADP+ displaced both FAD and BrdUMP from the active site. In the resultant ThyX-NADP+ binary complex, the AMP moiety is bound in a deep pocket similar to that of the same moiety of FAD in the ternary complex, while the nicotinamide part of NADP+ is engaged in a limited number of contacts with ThyX. The additional 2′-phosphate group attached to the AMP ribose of NADP+ could be accommodated with minor rearrangement of water molecules. The newly introduced 2′-phosphate groups are engaged in water-mediated interactions across the non-crystallographic 2-fold axis of the ThyX tetramer, suggesting possibilities for design of high-affinity bivalent inhibitors of this intriguing enzyme.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Biology - Volume 360, Issue 1, 30 June 2006, Pages 1–6
نویسندگان
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