1cjb

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spinqualitylabelsall models 1cjb, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

MALARIAL PURINE PHOSPHORIBOSYLTRANSFERASE

Overview

Malaria is a leading cause of worldwide mortality from infectious disease., Plasmodium falciparum proliferation in human erythrocytes requires purine, salvage by hypoxanthine-guanine-xanthine phosphoribosyltransferase, (HGXPRTase). The enzyme is a target for the development of novel, antimalarials. Design and synthesis of transition-state analogue, inhibitors permitted cocrystallization with the malarial enzyme and, refinement of the complex to 2.0 A resolution. Catalytic site contacts in, the malarial enzyme are similar to those of human hypoxanthine-guanine, phosphoribosyltransferase (HGPRTase) despite distinct substrate, specificity. The crystal structure of malarial HGXPRTase with bound, inhibitor, pyrophosphate, and two Mg(2+) ions reveals features unique to, the transition-state analogue complex. Substrate-assisted catalysis occurs, by ribooxocarbenium stabilization from the O5' lone pair and a, pyrophosphate oxygen. A dissociative reaction coordinate path is, implicated in which the primary reaction coordinate motion is the ribosyl, C1' in motion between relatively immobile purine base and, (Mg)(2)-pyrophosphate. Several short hydrogen bonds form in the complex of, the enzyme and inhibitor. The proton NMR spectrum of the transition-state, analogue complex of malarial HGXPRTase contains two downfield signals at, 14.3 and 15.3 ppm. Despite the structural similarity to the human enzyme, the NMR spectra of the complexes reveal differences in hydrogen bonding, between the transition-state analogue complexes of the human and malarial, HG(X)PRTases. The X-ray crystal structures and NMR spectra reveal chemical, and structural features that suggest a strategy for the design of, malaria-specific transition-state inhibitors.

About this Structure

1CJB is a Single protein structure of sequence from Plasmodium falciparum with MG, IRP and POP as ligands. Active as Hypoxanthine phosphoribosyltransferase, with EC number 2.4.2.8 Full crystallographic information is available from OCA.

Reference

The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor., Shi W, Li CM, Tyler PC, Furneaux RH, Cahill SM, Girvin ME, Grubmeyer C, Schramm VL, Almo SC, Biochemistry. 1999 Aug 3;38(31):9872-80. PMID:10433693

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