3BPR

Crystal structure of catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor C52

Summary for 3BPR

• Entry DOI: 10.2210/pdb3bpr/pdb
• Related: 2P0C 3BRB
• Descriptor: Proto-oncogene tyrosine-protein kinase MER, 2-(2-HYDROXYETHYLAMINO)-6-(3-CHLOROANILINO)-9-ISOPROPYLPURINE, SODIUM ION, ... (5 entities in total)
• Functional Keywords: atp-binding, disease mutation, glycoprotein, kinase, nucleotide-binding, phosphorylation, proto-oncogene, receptor, retinitis pigmentosa, sensory transduction, transferase, tyrosine-protein kinase, vision, structural genomics, structural genomics consortium, sgc, immunoglobulin domain, membrane, phosphoprotein, polymorphism, transmembrane
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein (By similarity): Q12866
• Total number of polymer chains: 4
• Total formula weight: 145038.89

Authors

Walker, J.R.,Huang, X.,Finerty Jr, P.J.,Weigelt, J.,Arrowsmith, C.H.,Edwards, A.M.,Bochkarev, A.,Dhe-Paganon, S.,Structural Genomics Consortium (SGC) (deposition date: 2007-12-19, release date: 2008-01-29, Last modification date: 2023-08-30)

Primary citation

Huang, X.,Finerty, P.,Walker, J.R.,Butler-Cole, C.,Vedadi, M.,Schapira, M.,Parker, S.A.,Turk, B.E.,Thompson, D.A.,Dhe-Paganon, S.
Structural insights into the inhibited states of the Mer receptor tyrosine kinase.
J.Struct.Biol., 165:88-96, 2009

PubMed Abstract: 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.

PubMed: 19028587
DOI: 10.1016/j.jsb.2008.10.003

Experimental method

X-RAY DIFFRACTION (2.8 Å)