3EWC

Crystal Structure of adenosine deaminase from Plasmodial vivax in complex with MT-coformycin

Summary for 3EWC

• Entry DOI: 10.2210/pdb3ewc/pdb
• Related: 3EWD
• Descriptor: Adenosine deaminase, ZINC ION, (8R)-3-(5-S-methyl-5-thio-beta-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol, ... (4 entities in total)
• Functional Keywords: adenosine deaminase, mt-coformycin, methylthio-coformycin, hydrolase
• Biological source: Plasmodium vivax
• Total number of polymer chains: 1
• Total formula weight: 43234.98

Authors

Schramm, V.L.,Almo, S.C.,Cassera, M.B.,Ho, M.C. (deposition date: 2008-10-14, release date: 2009-09-22, Last modification date: 2023-12-27)

Primary citation

Ho, M.C.,Cassera, M.B.,Madrid, D.C.,Ting, L.M.,Tyler, P.C.,Kim, K.,Almo, S.C.,Schramm, V.L.
Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases.
Biochemistry, 48:9618-9626, 2009

PubMed Abstract: Plasmodium falciparum is a purine auxotroph requiring hypoxanthine as a key metabolic precursor. Erythrocyte adenine nucleotides are the source of the purine precursors, making adenosine deaminase (ADA) a key enzyme in the pathway of hypoxanthine formation. Methylthioadenosine (MTA) is a substrate for most malarial ADAs, but not for human ADA. The catalytic site specificity of malarial ADAs permits methylthiocoformycin (MT-coformycin) to act as a Plasmodium-specific transition state analogue with low affinity for human ADA [Tyler, P. C., Taylor, E. A., Frohlich, R. G. G., and Schramm, V. L. (2007) J. Am. Chem. Soc. 129, 6872-6879]. The structural basis for MTA and MT-coformycin specificity in malarial ADAs is the subject of speculation [Larson, E. T., et al. (2008) J. Mol. Biol. 381, 975-988]. Here, the crystal structure of ADA from Plasmodium vivax (PvADA) in a complex with MT-coformycin reveals an unprecedented binding geometry for 5'-methylthioribosyl groups in the malarial ADAs. Compared to malarial ADA complexes with adenosine or deoxycoformycin, 5'-methylthioribosyl groups are rotated 130 degrees . A hydrogen bonding network between Asp172 and the 3'-hydroxyl of MT-coformycin is essential for recognition of the 5'-methylthioribosyl group. Water occupies the 5'-hydroxyl binding site when MT-coformycin is bound. Mutagenesis of Asp172 destroys the substrate specificity for MTA and MT-coformycin. Kinetic, mutagenic, and structural analyses of PvADA and kinetic analysis of five other Plasmodium ADAs establish the unique structural basis for its specificity for MTA and MT-coformycin. Plasmodium gallinaceum ADA does not use MTA as a substrate, is not inhibited by MT-coformycin, and is missing Asp172. Treatment of P. falciparum cultures with coformycin or MT-coformycin in the presence of MTA is effective in inhibiting parasite growth.

PubMed: 19728741
DOI: 10.1021/bi9012484

Experimental method

X-RAY DIFFRACTION (2.11 Å)