1y6r

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
(New page: 200px<br /><applet load="1y6r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y6r, resolution 2.20&Aring;" /> '''Crystal structure of...)
Line 1: Line 1:
-
[[Image:1y6r.gif|left|200px]]<br /><applet load="1y6r" size="450" color="white" frame="true" align="right" spinBox="true"
+
[[Image:1y6r.gif|left|200px]]<br /><applet load="1y6r" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1y6r, resolution 2.20&Aring;" />
caption="1y6r, resolution 2.20&Aring;" />
'''Crystal structure of MTA/AdoHcy nucleosidase complexed with MT-ImmA.'''<br />
'''Crystal structure of MTA/AdoHcy nucleosidase complexed with MT-ImmA.'''<br />
==Overview==
==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.
+
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==
==About this Structure==
-
1Y6R is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with MTM as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Y6R OCA].
+
1Y6R is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=MTM:'>MTM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y6R OCA].
==Reference==
==Reference==
Line 13: Line 13:
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
[[Category: Single protein]]
[[Category: Single protein]]
-
[[Category: Cornell, K.A.]]
+
[[Category: Cornell, K A.]]
-
[[Category: Evans, G.B.]]
+
[[Category: Evans, G B.]]
-
[[Category: Furneaux, R.H.]]
+
[[Category: Furneaux, R H.]]
-
[[Category: Howell, P.L.]]
+
[[Category: Howell, P L.]]
-
[[Category: Lee, J.E.]]
+
[[Category: Lee, J E.]]
-
[[Category: Riscoe, M.K.]]
+
[[Category: Riscoe, M K.]]
-
[[Category: Schramm, V.L.]]
+
[[Category: Schramm, V L.]]
[[Category: Singh, V.]]
[[Category: Singh, V.]]
-
[[Category: Tyler, P.C.]]
+
[[Category: Tyler, P C.]]
[[Category: MTM]]
[[Category: MTM]]
[[Category: mixed alpha/beta]]
[[Category: mixed alpha/beta]]
-
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 06:36:33 2007''
+
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:02:16 2008''

Revision as of 14:02, 21 February 2008


1y6r, resolution 2.20Å

Drag the structure with the mouse to rotate

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 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

Page seeded by OCA on Thu Feb 21 16:02:16 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Personal tools