Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

2WWI

Plasmodium falciparum thymidylate kinase in complex with AZTMP and ADP

Summary for 2WWI
Entry DOI10.2210/pdb2wwi/pdb
Related2WWF 2WWG 2WWH
DescriptorTHYMIDILATE KINASE, PUTATIVE, 3'-AZIDO-3'-DEOXYTHYMIDINE-5'-MONOPHOSPHATE, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
Functional Keywordstransferase, kinase, malaria
Biological sourcePLASMODIUM FALCIPARUM
Total number of polymer chains3
Total formula weight77174.24
Authors
Primary citationWhittingham, J.L.,Carrero-Lerida, J.,Brannigan, J.A.,Ruiz-Perez, L.M.,Silva, A.P.G.,Fogg, M.J.,Wilkinson, A.J.,Gilbert, I.H.,Wilson, K.S.,Gonzalez-Pacanowska, D.
Structural Basis for the Efficient Phosphorylation of Aztmp and Dgmp by Plasmodium Falciparum Type I Thymidylate Kinase.
Biochem.J., 428:499-, 2010
Cited by
PubMed Abstract: Plasmodium falciparum is the causative agent of malaria, a disease where new drug targets are required due to increasing resistance to current anti-malarials. TMPK (thymidylate kinase) is a good candidate as it is essential for the synthesis of dTTP, a critical precursor of DNA and has been much studied due to its role in prodrug activation and as a drug target. Type I TMPKs, such as the human enzyme, phosphorylate the substrate AZT (3'-azido-3'-deoxythymidine)-MP (monophosphate) inefficiently compared with type II TMPKs (e.g. Escherichia coli TMPK). In the present paper we report that eukaryotic PfTMPK (P. falciparum TMPK) presents sequence features of a type I enzyme yet the kinetic parameters for AZT-MP phosphorylation are similar to those of the highly efficient E. coli enzyme. Structural information shows that this is explained by a different juxtaposition of the P-loop and the azide of AZT-MP. Subsequent formation of the transition state requires no further movement of the PfTMPK P-loop, with no steric conflicts for the azide moiety, allowing efficient phosphate transfer. Likewise, we present results that confirm the ability of the enzyme to uniquely accept dGMP as a substrate and shed light on the basis for its wider substrate specificity. Information resulting from two ternary complexes (dTMP-ADP and AZT-MP-ADP) and a binary complex with the transition state analogue AP5dT [P1-(5'-adenosyl)-P5-(5'-thymidyl) pentaphosphate] all reveal significant differences with the human enzyme, notably in the lid region and in the P-loop which may be exploited in the rational design of Plasmodium-specific TMPK inhibitors with therapeutic potential.
PubMed: 20353400
DOI: 10.1042/BJ20091880
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.99 Å)
Structure validation

227933

PDB entries from 2024-11-27

PDB statisticsPDBj update infoContact PDBjnumon