PDBsum entry 5k5x

Transferase

PDB id: 5k5x

Contents

Protein chain

345 a.a.

Ligands

SO4 ×3

Waters ×148

PDB id:

5k5x

Name:

Transferase

Title:

Crystal structure of human pdgfra

Structure:

Platelet-derived growth factor receptor alpha. Chain: a. Fragment: unp residues 550-696,769-973. Synonym: pdgfr-alpha,alpha platelet-derived growth factor receptor, alpha-type platelet-derived growth factor receptor,cd140 antigen-like family member a,cd140a antigen,platelet-derived growth factor alpha receptor,platelet-derived growth factor receptor 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pdgfra, pdgfr2, rhepdgfra. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.17Å R-factor: 0.193 R-free: 0.224

Authors:

X.E.Yan,L.Liang,C.H.Yun

Key ref:

L.Liang et al. (2016). Structural and biochemical studies of the PDGFRA kinase domain. Biochem Biophys Res Commun, 477, 667-672. PubMed id: 27349873 DOI: 10.1016/j.bbrc.2016.06.117

Date:

24-May-16 Release date: 17-Aug-16

Protein chain

P16234  (PGFRA_HUMAN) -  Platelet-derived growth factor receptor alpha from Homo sapiens

Seq: 1089 a.a.

Struc: 345 a.a.

Enzyme reactions

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

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

Added reference

DOI no: 10.1016/j.bbrc.2016.06.117

Biochem Biophys Res Commun 477:667-672 (2016)

PubMed id: 27349873

Structural and biochemical studies of the PDGFRA kinase domain.

L.Liang, X.E.Yan, Y.Yin, C.H.Yun.

ABSTRACT

Platelet-derived growth factor receptor α (PDGFRA) is a Type III receptor tyrosine kinase, and this kinase is a target for treatment of gastrointestinal stromal tumors (GIST) as it is frequently mutated in these cancers. Most of the mutations that cause constitutive activation of PDGFRA occur in either the activation loop (A-loop) or in the juxtamembrane (JM) domain, such as the mutations D842V or V561D respectively. Treatment of PDGFRA-mutated GIST with imatinib is successful in some cases, but the D842V mutation is imatinib-resistant. To better understand the mechanism of PDGFRA drug-resistance, we have determined the crystal structure of the PDGFRA kinase domain in the auto-inhibited form, and studied the kinetics of the D842V mutation. Auto-inhibited PDGFRA is stabilized by the JM domain, which inserts into the active site of the kinase. The conserved residue Asp842 makes extensive contacts with several A-loop residues to maintain PDGFRA in the "DFG out" conformation, which stabilizes the kinase in the inactive state and facilitates the binding of imatinib. The D842V mutation would therefore be expected to activate the kinase and hinder the binding of drug through destabilizing the "DFG out" conformation. Furthermore, our kinetic data show that drug resistance in the D842V mutation may also in part result from its increased affinity for ATP. The PDGFRA kinase domain structure we report in this study has potential to facilitate development of new agents which can inhibit this kinase, including both its activating and drug-resistant mutations.