Transition-state complex of the purine-specific nucleoside hydrolase of T. vivax: enzyme conformational changes and implications for catalysis

Journal of Molecular Biology
W VerséesJ Steyaert

Abstract

Nucleoside hydrolases cleave the N-glycosidic bond of ribonucleosides. Crystal structures of the purine-specific nucleoside hydrolase from Trypanosoma vivax have previously been solved in complex with inhibitors or a substrate. All these structures show the dimeric T. vivax nucleoside hydrolase with an "open" active site with a highly flexible loop (loop 2) in its vicinity. Here, we present the crystal structures of the T. vivax nucleoside hydrolase with both soaked (TvNH-ImmH(soak)) and co-crystallised (TvNH-ImmH(co)) transition-state inhibitor immucillin H (ImmH or (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol) to 2.1 A and 2.2 A resolution, respectively. In the co-crystallised structure, loop 2 is ordered and folds over the active site, establishing previously unobserved enzyme-inhibitor interactions. As such this structure presents the first complete picture of a purine-specific NH active site, including leaving group interactions. In the closed active site, a water channel of highly ordered water molecules leads out from the N7 of the nucleoside toward bulk solvent, while Trp260 approaches the nucleobase in a tight parallel stacking interaction. Together with mutagenesis results, this structure rules out...Continue Reading

References

Nov 5, 1991·Biochemistry·B A HorensteinV L Schramm
Mar 14, 1991·Nature·J R Knowles
Jul 1, 1990·Acta Crystallographica. Section A, Foundations of Crystallography·A T BrüngerJ W Erickson
Mar 25, 1970·Journal of the American Chemical Society·J A ZoltewiczG Grahe
Nov 1, 1984·Molecular and Biochemical Parasitology·D J Hammond, W E Gutteridge
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Oct 6, 1998·Annual Review of Biochemistry·V L Schramm
Jan 16, 1999·Biochemistry·G P WangC Grubmeyer
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·A A VaguineS J Wodak
Apr 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·G A KicskaH L Kaufman
Feb 21, 2002·The Journal of Biological Chemistry·Wim VerséesJan Steyaert
Dec 6, 2002·Journal of the American Chemical Society·Devleena Mazumder, Thomas C Bruice
Aug 20, 2003·Accounts of Chemical Research·Vern L Schramm
Aug 30, 2003·Science·Stephen J Benkovic, Sharon Hammes-Schiffer
Dec 17, 2003·Current Opinion in Structural Biology·Wim Versées, Jan Steyaert
Jan 1, 2004·Chemistry & Biology·Eric M BennettSteven E Ealick
Mar 31, 2004·Journal of Molecular Biology·Wim VerséesJan Steyaert
Dec 8, 2004·Archives of Biochemistry and Biophysics·Vern L Schramm
Feb 8, 2005·The Journal of Biological Chemistry·Stefan LoverixWim Versées
Mar 30, 2005·Proceedings of the National Academy of Sciences of the United States of America·Dan McElhenyPeter E Wright
Apr 5, 2005·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoyRandy J Read
Nov 4, 2005·Nature·Elan Z EisenmesserDorothee Kern

❮ Previous
Next ❯

Citations

Mar 3, 2010·Antimicrobial Agents and Chemotherapy·Maya BergKoen Augustyns
Jul 31, 2013·Acta Crystallographica. Section D, Biological Crystallography·Francesca GianneseMassimo Degano
Jun 4, 2008·The Journal of Biological Chemistry·An VandemeulebrouckeWim Versées
Dec 22, 2009·Chemical Communications : Chem Comm·Mayca OnegaDavid O'Hagan
Mar 29, 2007·The Journal of Physical Chemistry. B·Andrea L MillenStacey D Wetmore
Feb 14, 2008·Biochemistry·Mahmoud GhanemVern L Schramm
Sep 10, 2010·Biochemistry·An VandemeulebrouckeMassimo Degano
Jun 22, 2007·European Journal of Medicinal Chemistry·A GoeminneK Augustyns
Nov 18, 2015·Journal of Chemical Theory and Computation·Nanhao ChenZexing Cao
Jan 20, 2012·The Journal of Physical Chemistry. B·Ruibo WuZexing Cao
Oct 20, 2018·Chemical Reviews·Vern L Schramm
Mar 14, 2009·Biochimica Et Biophysica Acta·Wim VerséesJan Steyaert
Apr 8, 2009·Biochimica Et Biophysica Acta·John N BarlowJan Steyaert
Sep 6, 2012·European Journal of Medicinal Chemistry·Magdalena Nascimento RennóJosé Daniel Figueroa-Villar

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cajal Bodies & Gems

Cajal bodies or coiled bodies are dense foci of coilin protein. Gemini of Cajal bodies, or gems, are microscopically similar to Cajal bodies. It is believed that Cajal bodies play important roles in RNA processing while gems assist the Cajal bodies. Find the latest research on Cajal bodies and gems here.