Polo-like kinase 1 (Plk1) is a serine/threonine protein kinase mediating cell mitosis. Overexpression of Plk1 is observed in human cancers, thus becoming an antitumor drug target. The Plk1 contains an N-terminal kinase domain (KD) and a C-terminal polo-box domain (PBD). While high-resolution structures of individual domains are available, the structure of a KD-PBD interacting complex by which novel PBD-binding inhibitors  identified in-house allosterically regulate kinase activities remains elusive. By combining small-angle X-ray scattering, hydroxyl radical protein footprinting, and computational modeling, we are now able to determine the multidomain architecture of the full-length human Plk1, critical for the design of certain mutations at the domain-interacting interface to alter its enzyme activity and for the design of novel Plk1 inhibitors.<br/>

Integrative structural modeling of multidomain polo-like kinase 1

2019 Spring National Meeting

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