Crystal Structure of the Brugia malayi Thymidylate Kinase-dTMP Complex and Small Angle X-ray Scattering Experiments Identifies Changes in the Dimeric Association Compared to the Human Homolog
J. Vishwakarma, V. K. Sharma, S. Kumar, R. Ramachandran
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引用次数: 0
Abstract
Abstract—
Lymphatic filariasis is a serious parasitic disease spread by mosquitoes and affects the lymphatic system resulting in abnormal enlargement of body parts. It is caused by three related nematodes, one of which is Brugia malayi. Thymidylate kinase (TMK) is the principal enzyme involved in nucleic acid metabolism. It synthesizes pyrimidine by catalyzing the phosphorylation of thymidine-5'-monophosphate (dTMP) to form thymidine-5'-diphosphate (dTDP) in the presence of Mg2+ and ATP. Hence TMK could be an attractive drug target to develop new anti-filarials. Here, we report the crystal structure of dTMP substrate bound Brugia malayi thymidylate kinase (BmTMK) to 1.91 Å resolution. The structure adopts the classic α/β fold like P-loop NTPases with core and Nucleotide binding domains. A comparison with the human homolog shows several differences in the TMK binding site and also in the dimeric association. Small-angle X-ray scattering (SAXS) experiments support the differences in the dimeric association between BmTMK and its human counterpart. The differences in the active site architecture can possibly be exploited to develop BmTMK specific inhibitors.
期刊介绍:
Crystallography Reports is a journal that publishes original articles short communications, and reviews on various aspects of crystallography: diffraction and scattering of X-rays, electrons, and neutrons, determination of crystal structure of inorganic and organic substances, including proteins and other biological substances; UV-VIS and IR spectroscopy; growth, imperfect structure and physical properties of crystals; thin films, liquid crystals, nanomaterials, partially disordered systems, and the methods of studies.