5LOH

Kinase domain of human Greatwall

Summary for 5LOH

• Entry DOI: 10.2210/pdb5loh/pdb
• Descriptor: Serine/threonine-protein kinase greatwall,Serine/threonine-protein kinase greatwall, STAUROSPORINE, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: kinase domain, inhibitor, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: Q96GX5
• Total number of polymer chains: 2
• Total formula weight: 77583.74

Authors

Rajasekaran, M.B.,Pearl, L.H.,Oliver, A.W. (deposition date: 2016-08-09, release date: 2016-09-07, Last modification date: 2024-01-10)

Primary citation

Ocasio, C.A.,Rajasekaran, M.B.,Walker, S.,Le Grand, D.,Spencer, J.,Pearl, F.M.,Ward, S.E.,Savic, V.,Pearl, L.H.,Hochegger, H.,Oliver, A.W.
A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct.
Oncotarget, 7:71182-71197, 2016

PubMed Abstract: MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors.

PubMed: 27563826
DOI: 10.18632/oncotarget.11511

Experimental method

X-RAY DIFFRACTION (3.1 Å)