3BPR

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

3BPR の概要

• エントリーDOI: 10.2210/pdb3bpr/pdb
• 関連するPDBエントリー: 2P0C 3BRB
• 分子名称: Proto-oncogene tyrosine-protein kinase MER, 2-(2-HYDROXYETHYLAMINO)-6-(3-CHLOROANILINO)-9-ISOPROPYLPURINE, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein (By similarity): Q12866
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 145038.89

構造登録者

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) (登録日: 2007-12-19, 公開日: 2008-01-29, 最終更新日: 2023-08-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)