PDBsum entry 3gqi

Transferase/transferase inhibitor

PDB id: 3gqi

Contents

Protein chains

307 a.a. *

226 a.a. *

Ligands

DVT

ACP

Metals

_MG

Waters ×77

* Residue conservation analysis

PDB id:

3gqi

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of activated receptor tyrosine kinase in complex with substrates

Structure:

Basic fibroblast growth factor receptor 1. Chain: a. Fragment: protein kinase domain. Synonym: fgfr-1, bfgf-r, fms-like tyrosine kinase 2, c-fgr. Engineered: yes. Mutation: yes. PhospholipasE C-gamma-1. Chain: b. Fragment: tandem sh2 domains.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfbr, fgfr1, flg, flt2. Expressed in: escherichia coli. Expression_system_taxid: 562. Rattus norvegicus. Rat. Organism_taxid: 10116.

Resolution:

2.50Å R-factor: 0.249 R-free: 0.289

Authors:

J.H.Bae,E.D.Lew,S.Yuzawa,F.Tome,I.Lax,J.Schlessinger

Key ref:

J.H.Bae et al. (2009). The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site. Cell, 138, 514-524. PubMed id: 19665973

Date:

24-Mar-09 Release date: 18-Aug-09

Protein chain

P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1 from Homo sapiens

Seq: 822 a.a.

Struc: 307 a.a.*

Protein chain

P10686  (PLCG1_RAT) -  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 from Rattus norvegicus

Seq: 1290 a.a.

Struc: 226 a.a.

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chain A: 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 = ACP) matches with 81.25% similarity) + ADP + H(+)

• Enzyme class 2: Chain B: E.C.3.1.4.11 - phosphoinositide phospholipase C.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = 1D-myo-inositol 1,4,5-trisphosphate + a 1,2-diacyl-sn-glycerol + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

Cell 138:514-524 (2009)

PubMed id: 19665973

The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site.

J.H.Bae, E.D.Lew, S.Yuzawa, F.Tomé, I.Lax, J.Schlessinger.

ABSTRACT

SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY containing peptides may not account for and likely represents an oversimplified mechanism for regulation of selectivity of signaling pathways in living cells. Here we describe the crystal structure of the activated tyrosine kinase domain of FGFR1 in complex with a phospholipase Cgamma fragment. The structural and biochemical data and experiments with cultured cells show that the selectivity of phospholipase Cgamma binding and signaling via activated FGFR1 are determined by interactions between a secondary binding site on an SH2 domain and a region in FGFR1 kinase domain in a phosphorylation independent manner. These experiments reveal a mechanism for how SH2 domain selectivity is regulated in vivo to mediate a specific cellular process.