PDBsum entry 3brb

Transferase

PDB id: 3brb

Contents

Protein chains

260 a.a. *

271 a.a. *

Ligands

ADP ×2

GOL

Metals

_CL ×5

_MG ×2

Waters ×236

* Residue conservation analysis

PDB id:

3brb

Name:

Transferase

Title:

Crystal structure of catalytic domain of the proto-oncogene tyrosine- protein kinase mer in complex with adp

Structure:

Proto-oncogene tyrosine-protein kinase mer. Chain: a, b. Fragment: catalytic domain: residues 574-864. Synonym: c-mer, receptor tyrosine kinase mertk. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: peripheral blood leukocyte. Gene: mertk, mer. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.90Å R-factor: 0.195 R-free: 0.240

Authors:

J.R.Walker,X.Huang,P.J.Finerty Jr,J.Weigelt,C.H.Arrowsmith, A.M.Edwards,A.Bochkarev,S.Dhe-Paganon,Structural Genomics Consortium (Sgc)

Key ref:

X.Huang et al. (2009). Structural insights into the inhibited states of the Mer receptor tyrosine kinase. J Struct Biol, 165, 88-96. PubMed id: 19028587

Date:

21-Dec-07 Release date: 22-Jan-08

Protein chain

Q12866  (MERTK_HUMAN) -  Tyrosine-protein kinase Mer from Homo sapiens

Seq: 999 a.a.

Struc: 260 a.a.

Protein chain

Q12866  (MERTK_HUMAN) -  Tyrosine-protein kinase Mer from Homo sapiens

Seq: 999 a.a.

Struc: 271 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Struct Biol 165:88-96 (2009)

PubMed id: 19028587

Structural insights into the inhibited states of the Mer receptor tyrosine kinase.

X.Huang, P.Finerty, J.R.Walker, C.Butler-Cole, M.Vedadi, M.Schapira, S.A.Parker, B.E.Turk, D.A.Thompson, S.Dhe-Paganon.

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.