PDBsum entry 4lrm

Transferase/transferase inhibitor

PDB id: 4lrm

Contents

Protein chains

307 a.a.

289 a.a.

Ligands

YUN ×5

Waters ×16

PDB id:

4lrm

Name:

Transferase/transferase inhibitor

Title:

Egfr d770_n771insnpg in complex with pd168393

Structure:

Epidermal growth factor receptor. Chain: a, b, c, d, e. Fragment: epidermal growth factor receptor (unp residues 694-1022). Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

3.53Å R-factor: 0.227 R-free: 0.264

Authors:

C.H.Yun,M.J.Eck

Key ref:

H.Yasuda et al. (2013). Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med, 5, 216ra177. PubMed id: 24353160 DOI: 10.1126/scitranslmed.3007205

Date:

20-Jul-13 Release date: 15-Jan-14

Protein chains

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 307 a.a.*

Protein chains

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 289 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E: 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: 10.1126/scitranslmed.3007205

Sci Transl Med 5:216ra177 (2013)

PubMed id: 24353160

Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.

H.Yasuda, E.Park, C.H.Yun, N.J.Sng, A.R.Lucena-Araujo, W.L.Yeo, M.S.Huberman, D.W.Cohen, S.Nakayama, K.Ishioka, N.Yamaguchi, M.Hanna, G.R.Oxnard, C.S.Lathan, T.Moran, L.V.Sequist, J.E.Chaft, G.J.Riely, M.E.Arcila, R.A.Soo, M.Meyerson, M.J.Eck, S.S.Kobayashi, D.B.Costa.

ABSTRACT

Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.