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Crystal structure of human vaccinia‐related kinase 1 in complex with AMP‐PNP, a non‐hydrolyzable ATP analog
Author(s) -
Ngow Yeen Shian,
Rajan Sreekanth,
Ye Hong,
Yoon Ho Sup
Publication year - 2019
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.3552
Subject(s) - kinase , adenosine triphosphate , biochemistry , chemistry , serine , enzyme , biology , microbiology and biotechnology , stereochemistry
Vaccinia‐related kinase 1 (VRK1), a serine/threonine mitotic kinase, is widely over‐expressed in dividing cells and regarded as a cancer drug target primarily due to its function as an early response gene in cell proliferation. However, the mechanism of VRK1 phosphorylation and substrate activation is not well understood. More importantly even the molecular basis of VRK1 interaction with its cofactor, adenosine triphosphate (ATP), is unavailable to‐date. As designing specific inhibitors remains to be the major challenge in kinase research, such a molecular understanding will enable us to design ATP‐competitive specific inhibitors of VRK1. Here we report the molecular characterization of VRK1 in complex with AMP‐PNP, a non‐hydrolyzable ATP‐analog, using NMR titration followed by the co‐crystal structure determined upto 2.07 Å resolution. We also carried out the structural comparison of the AMP‐PNP bound‐form with its apo and inhibitor‐bound counterparts, which has enabled us to present our rationale toward designing VRK1‐specific inhibitors.