2WWG

Plasmodium falciparum thymidylate kinase in complex with dGMP and ADP

Summary for 2WWG

• Entry DOI: 10.2210/pdb2wwg/pdb
• Related: 2WWF 2WWH 2WWI
• Descriptor: THYMIDILATE KINASE, PUTATIVE, 2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE, ADENOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: transferase, kinase, malaria
• Biological source: PLASMODIUM FALCIPARUM
• Total number of polymer chains: 3
• Total formula weight: 78693.59

Authors

Whittingham, J.L.,Carrero-Lerida, J.,Brannigan, J.A.,Ruiz-Perez, L.M.,Silva, A.P.,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.,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

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)