1Y6Q

Cyrstal structure of MTA/AdoHcy nucleosidase complexed with MT-DADMe-ImmA

Summary for 1Y6Q

• Entry DOI: 10.2210/pdb1y6q/pdb
• Descriptor: MTA/SAH nucleosidase, CHLORIDE ION, (3R,4S)-1-[(4-AMINO-5H-PYRROLO[3,2-D]PYRIMIDIN-7-YL)METHYL]-4-[(METHYLSULFANYL)METHYL]PYRROLIDIN-3-OL, ... (4 entities in total)
• Functional Keywords: mixed alpha/beta dimer, hydrolase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 51633.93

Authors

Lee, J.E.,Singh, V.,Evans, G.B.,Tyler, P.C.,Furneaux, R.H.,Cornell, K.A.,Riscoe, M.K.,Schramm, V.L.,Howell, P.L. (deposition date: 2004-12-06, release date: 2005-03-01, Last modification date: 2023-08-23)

Primary citation

Lee, J.E.,Singh, V.,Evans, G.B.,Tyler, P.C.,Furneaux, R.H.,Cornell, K.A.,Riscoe, M.K.,Schramm, V.L.,Howell, P.L.
Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase.
J.Biol.Chem., 280:18274-18282, 2005

PubMed 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 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.

PubMed: 15746096
DOI: 10.1074/jbc.M414471200

Experimental method

X-RAY DIFFRACTION (2.2 Å)