2WWI
Plasmodium falciparum thymidylate kinase in complex with AZTMP and ADP
Summary for 2WWI
Entry DOI | 10.2210/pdb2wwi/pdb |
Related | 2WWF 2WWG 2WWH |
Descriptor | THYMIDILATE KINASE, PUTATIVE, 3'-AZIDO-3'-DEOXYTHYMIDINE-5'-MONOPHOSPHATE, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total) |
Functional Keywords | transferase, kinase, malaria |
Biological source | PLASMODIUM FALCIPARUM |
Total number of polymer chains | 3 |
Total formula weight | 77174.24 |
Authors | Whittingham, 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. (deposition date: 2009-10-23, release date: 2010-04-21, Last modification date: 2023-12-20) |
Primary citation | Whittingham, 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: 20353400DOI: 10.1042/BJ20091880 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.99 Å) |
Structure validation
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