1b8o
From Proteopedia
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'''PURINE NUCLEOSIDE PHOSPHORYLASE''' | '''PURINE NUCLEOSIDE PHOSPHORYLASE''' | ||
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[[Category: Shi, W.]] | [[Category: Shi, W.]] | ||
[[Category: Tyler, P C.]] | [[Category: Tyler, P C.]] | ||
| - | [[Category: | + | [[Category: Pentosyltransferase]] |
| - | [[Category: | + | [[Category: Purine nucleoside phosphorylase]] |
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Revision as of 08:12, 2 May 2008
PURINE NUCLEOSIDE PHOSPHORYLASE
Overview
Immucillin-H [ImmH; (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol] is a 23 pM inhibitor of bovine purine nucleoside phosphorylase (PNP) specifically designed as a transition state mimic [Miles, R. W., Tyler, P. C., Furneaux, R. H., Bagdassarian, C. K., and Schramm, V. L. (1998) Biochemistry 37, 8615-8621]. Cocrystals of PNP and the inhibitor are used to provide structural information for each step through the reaction coordinate of PNP. The X-ray crystal structure of free ImmH was solved at 0.9 A resolution, and a complex of PNP.ImmH.PO(4) was solved at 1.5 A resolution. These structures are compared to previously reported complexes of PNP with substrate and product analogues in the catalytic sites and with the experimentally determined transition state structure. Upon binding, ImmH is distorted to a conformation favoring ribosyl oxocarbenium ion formation. Ribosyl destabilization and transition state stabilization of the ribosyl oxocarbenium ion occur from neighboring group interactions with the phosphate anion and the 5'-hydroxyl of the ribosyl group. Leaving group activation of hypoxanthine involves hydrogen bonds to O6, N1, and N7 of the purine ring. Ordered water molecules provide a proton transfer bridge to O6 and N7 and permit reversible formation of these hydrogen bonds. Contacts between PNP and catalytic site ligands are shorter in the transition state analogue complex of PNP.ImmH.PO(4) than in the Michaelis complexes of PNP.inosine.SO(4) or PNP.hypoxanthine.ribose 1-PO(4). Reaction coordinate motion is dominated by translation of the carbon 1' of ribose between relatively fixed phosphate and purine groups. Purine and pyrimidine phosphoribosyltransferases and nucleoside N-ribosyl hydrolases appear to operate by a similar mechanism.
About this Structure
1B8O is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
Transition state structure of purine nucleoside phosphorylase and principles of atomic motion in enzymatic catalysis., Fedorov A, Shi W, Kicska G, Fedorov E, Tyler PC, Furneaux RH, Hanson JC, Gainsford GJ, Larese JZ, Schramm VL, Almo SC, Biochemistry. 2001 Jan 30;40(4):853-60. PMID:11170405 Page seeded by OCA on Fri May 2 11:12:45 2008
