Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5′-methylthioadenosine/S- adenosylhomocysteine nucleosidase

Jeffrey E. Lee, Vipender Singh, Gary B. Evans, Peter C. Tyler, Richard H. Furneax, Kenneth A. Cornell, Michael Riscoe, Vern L. Schramm, P. Lynne Howell

Research output: Contribution to journalArticle

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Abstract

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 Ki* 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 Å 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 off 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.

Original languageEnglish (US)
Pages (from-to)18274-18282
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number18
DOIs
StatePublished - May 6 2005
Externally publishedYes

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adenosylhomocysteine nucleosidase
Escherichia coli
Purine-Nucleoside Phosphorylase
Ions
Atoms
Nucleophiles
Structural analysis
Hydrogen
Hydrogen bonds
Substitution reactions
Crystal structure

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5′-methylthioadenosine/S- adenosylhomocysteine nucleosidase. / Lee, Jeffrey E.; Singh, Vipender; Evans, Gary B.; Tyler, Peter C.; Furneax, Richard H.; Cornell, Kenneth A.; Riscoe, Michael; Schramm, Vern L.; Howell, P. Lynne.

In: Journal of Biological Chemistry, Vol. 280, No. 18, 06.05.2005, p. 18274-18282.

Research output: Contribution to journalArticle

Lee, Jeffrey E. ; Singh, Vipender ; Evans, Gary B. ; Tyler, Peter C. ; Furneax, Richard H. ; Cornell, Kenneth A. ; Riscoe, Michael ; Schramm, Vern L. ; Howell, P. Lynne. / Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5′-methylthioadenosine/S- adenosylhomocysteine nucleosidase. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 18. pp. 18274-18282.
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abstract = "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 Ki* 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 {\AA} 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 off 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.",
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AU - Lee, Jeffrey E.

AU - Singh, Vipender

AU - Evans, Gary B.

AU - Tyler, Peter C.

AU - Furneax, Richard H.

AU - Cornell, Kenneth A.

AU - Riscoe, Michael

AU - Schramm, Vern L.

AU - Howell, P. Lynne

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N2 - 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 Ki* 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 Å 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 off 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.

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