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The structural basis of unique substrate recognition by Plasmodium thymidylate kinase: Molecular dynamics simulation and inhibitory studies.

ABSTRACT: Plasmodium falciparum thymidylate kinase (PfTMK) showed structural and catalytic distinctions from the host enzyme rendering it a hopeful antiprotozoal drug target. Despite the comprehensive enzymologic, structural, inhibitory and chemical synthesis approaches targeting this enzyme, the elucidation of the exact mechanism underlying the recognition of the atypical purine substrates remains to be determined. In this study, molecular dynamics (MD) simulation of a broad range of substrates and inhibitors as well as the inhibitory properties of deoxyguanosine (dG) derivatives were used to assess the PfTMK substructure molecular rearrangements. The estimated changes during the favourable binding of high affinity substrate (TMP) include lower interaction with P-loop, free residue fluctuations of the lid domain and the average RMSD value. The RMSD of TMP complex was higher and more rapidly stabilized than the dGMP complex. The lid domain flexibility is severely affected by dGMP and ?-thymidine derivatives, while being partially fluctuating with other thymidine derivatives. The TMK-purine (dGMP) complex was slowly and gradually stabilized with lower over all structure flexibility and residue fluctuations especially at the lid domain, which closes the active site during its catalytic state. Thymidine derivatives allow structure flexibility of the lid domain being highly fluctuating in ?- and ?-thymidine derivatives and TMP. dG derivatives remains less efficient than thymidine derivatives in inhibiting TMK. The variations in the structural dynamics of the P-loop and lid domain in response to TMP or dGMP might favour thymidine-based compounds. The provided MD simulation strategy can be used for predicating structural changes in PfTMK during lead optimization.

SUBMITTER: Kandeel M

PROVIDER: S-EPMC6366710 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The structural basis of unique substrate recognition by Plasmodium thymidylate kinase: Molecular dynamics simulation and inhibitory studies.

Kandeel Mahmoud M Kitade Yukio Y Al-Taher Abdulla A Al-Nazawi Mohammed M

PloS one 20190207 2

Plasmodium falciparum thymidylate kinase (PfTMK) showed structural and catalytic distinctions from the host enzyme rendering it a hopeful antiprotozoal drug target. Despite the comprehensive enzymologic, structural, inhibitory and chemical synthesis approaches targeting this enzyme, the elucidation of the exact mechanism underlying the recognition of the atypical purine substrates remains to be determined. In this study, molecular dynamics (MD) simulation of a broad range of substrates and inhib ...[more]

PMID: 30730992

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Project description:Arginine kinase from the sea cucumber Stichopus japonicus underwent a unique molecular evolution. Unlike the monomeric 40 kDa arginine kinases from molluscs and arthropods, Stichopus arginine kinase is dimeric, the same as cytoplasmic isoenzymes of the vertebrate creatine kinases. Its entire amino acid sequence is more similar to creatine kinases than to other arginine kinases, but the guanidino specificity region (GS region) is of the arginine kinase type. To elucidate its unusual evolution, the structure of the Stichopus arginine kinase gene was determined. It consisted of seven exons and six introns, and a part of the exon 2 of the Stichopus gene corresponds to the GS region. Compared with the structure of the human muscle creatine kinase gene (seven exons, six introns), the splice junctions of five introns were conserved exactly between the two genes, suggesting that these introns had been conserved for at least 500 million years. The entire sequence of Stichopus arginine kinase is distinctly included in the creatine kinase cluster in all tree construction methods examined. On the other hand, if the tree is constructed only from sequences corresponding to Stichopus exon 2, it is placed in the arginine kinase cluster. Thus we conclude that Stichopus arginine kinase evolved not from the arginine kinase gene but from the creatine kinase gene, and suggest that its GS region, determining substrate specificity, has been replaced by an arginine kinase type via exon shuffling. In typical arginine kinases four residues, Ser(63), Gly(64), Val(65) and Tyr(68) (numbering from the Limulus polyphemus sequence), in the GS region are highly conserved and are associated with substrate binding. Among them, Tyr(68) appears to play a crucial role by forming a hydrogen bond with the substrate, and is conserved exactly in all arginine kinases. However, in Stichopus arginine kinase, none of these four conserved residues were present. Nevertheless, the enzyme displays an affinity for the substrate arginine (K(m)=0.8 mM) comparable with other arginine kinases. This implies that a completely different substrate-binding system has been developed in Stichopus arginine kinase. We propose that the His(64) in Stichopus arginine kinase acts as a substitute for the Tyr(68) in other arginine kinases, and that the imidazole ring of His(64) is hydrogen bonded with the substrate arginine, thus stabilizing it.

Dataset Information

The structural basis of unique substrate recognition by Plasmodium thymidylate kinase: Molecular dynamics simulation and inhibitory studies.

Publications

The structural basis of unique substrate recognition by Plasmodium thymidylate kinase: Molecular dynamics simulation and inhibitory studies.

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