2b1g

From Proteopedia

Revision as of 13:23, 23 January 2008

Crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase

Overview

The inosine monophosphate cyclohydrolase (IMPCH) component (residues, 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide, ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC), catalyzes the final step in the de novo purine biosynthesis pathway that, produces IMP. As a potential target for antineoplastic intervention, we, designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide, (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside, monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate, in the cyclization reaction. All compounds are competitive inhibitors, against IMPCH (K(i) values = 0.13-0.23 mum) with the simple heterocycle 1, exhibiting the most potent inhibition (K(i) = 0.13 mum). Crystal, structures of bifunctional ATIC in complex with nucleoside 2 and, nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH, feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler, heterocycle 1 had a completely different IMPCH binding mode and was, relocated to the phosphate binding pocket that was identified from, previous xanthosine 5'-monophosphate structures. The aromatic imidazole, ring interacts with a helix dipole, similar to the interaction with the, phosphate moiety of 3. The crystal structures not only revealed the, mechanism of inhibition of these compounds, but they now serve as a, platform for future inhibitor improvements. Importantly, the, nucleosidecomplexed structure supports the notion that inhibitors lacking, a negatively charged phosphate can still inhibit IMPCH activity with, comparable potency to phosphate-containing inhibitors. Provocatively, the, nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which, now provides a lead compound for the design of inhibitors that, simultaneously target both active sites of this bifunctional enzyme.

About this Structure

2B1G is a Single protein structure of sequence from Gallus gallus with , and as ligands. Full crystallographic information is available from OCA.

Reference

Structure-based Design, Synthesis, Evaluation, and Crystal Structures of Transition State Analogue Inhibitors of Inosine Monophosphate Cyclohydrolase., Xu L, Chong Y, Hwang I, D'Onofrio A, Amore K, Beardsley GP, Li C, Olson AJ, Boger DL, Wilson IA, J Biol Chem. 2007 Apr 27;282(17):13033-46. Epub 2007 Feb 26. PMID:17324932

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