1y6r
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(New page: 200px<br /><applet load="1y6r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y6r, resolution 2.20Å" /> '''Crystal structure of...)
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Revision as of 04:29, 21 November 2007
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Crystal structure of MTA/AdoHcy nucleosidase complexed with MT-ImmA.
Overview
Immucillin and DADMe-Immucillin inhibitors are tight binding transition, state mimics of purine nucleoside phosphorylases (PNP)., 5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is, proposed to form a similar transition state structure as PNP. The, companion paper describes modifications of the Immucillin and, DADMe-Immucillin inhibitors to better match transition state features of, MTAN and have led to 5'-thio aromatic substitutions that extend the, inhibition constants to the femtomolar range (Singh, V., Evans, G. B., Lenz, D. H., Mason, J., Clinch, K., Mee, S., Painter, G. F., Tyler, P. C., Furneaux, R. H., Lee, J. E., Howell, P. L., and Schramm, V. L. (2005) J., Biol. Chem. 280, 18265-18273). 5'-Methylthio-Immucillin A (MT-ImmA) and, 5'-methylthio-DADMe-Immucillin A (MT-DADMe-ImmA) exhibit slow-onset, inhibition with K(i)(*) of 77 and 2 pm, respectively, and were selected, for structural analysis as the parent compounds of each class of, transition state analogue. The crystal structures of Escherichia coli MTAN, complexed with MT-ImmA and MT-DADMe-ImmA were determined to 2.2 A, resolution and compared with the existing MTAN inhibitor complexes. These, MTAN-transition state complexes are among the tightest binding, enzyme-ligand complexes ever described and analysis of their mode of, binding provides extraordinary insight into the structural basis for their, affinity. The MTAN-MT-ImmA complex reveals the presence of a new ion pair, between the 4'-iminoribitol atom and the nucleophilic water (WAT3) that, captures key features of the transition state. Similarly, in the, MTAN-MT-DADMe-ImmA complex a favorable hydrogen bond or ion pair, interaction between the cationic 1'-pyrrolidine atom and WAT3 is crucial, for tight affinity. Distance analysis of the nucleophile and leaving group, show that MT-ImmA is a mimic of an early transition state, while, MT-DADMe-ImmA is a better mimic of the highly dissociated transition state, of E. coli MTAN.
About this Structure
1Y6R is a Single protein structure of sequence from Escherichia coli with MTM as ligand. Full crystallographic information is available from OCA.
Reference
Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase., Lee JE, Singh V, Evans GB, Tyler PC, Furneaux RH, Cornell KA, Riscoe MK, Schramm VL, Howell PL, J Biol Chem. 2005 May 6;280(18):18274-82. Epub 2005 Mar 3. PMID:15746096
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