Summary
PDB 3BPR deposited: 2007-12-19 modified: 2010-05-19
Title Crystal structure of catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor C52
Authors Butler-Cole, C., Dhe-Paganon, S., Finerty, P., Huang, X., Parker, S.A., Schapira, M., Thompson, D.A., Turk, B.E., Vedadi, M., Walker, J.R.
Method X-RAY DIFFRACTION
Structure factors resolution 2.8 rfactor 0.27361 rfree 0.30134
DPI 0.90 theoretical min: 0.56
Related PDB Entries 2P0C 3BRB
Citations

The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited alphaC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and alphaC-Glu-out conformation, but acquires other conformational changes. The alphaC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes.

J.Struct.Biol. 2009 Feb; 165(2):88-96 doi:10.1016/j.jsb.2008.10.003

Cross References
Database source Identifier Description
PubMed 19028587 JSBIEM
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3BPR/1 3BPR 1 monomer 0 1 1 1864
3BPR/2 3BPR 2 monomer 0 1 2 1860
3BPR/3 3BPR 3 monomer 0 1 2 1868
3BPR/4 3BPR 4 monomer 0 1 2 1849