PDBsum entry 4riy

Transferase

PDB id: 4riy

Contents

Protein chains

269 a.a.

293 a.a.

Ligands

ANP ×2

ADP ×2

Metals

_MG ×4

PDB id:

4riy

Name:

Transferase

Title:

Crystal structure of an egfr/her3 kinase domain heterodimer containing the cancer-associated her3-e909g mutation

Structure:

Receptor tyrosine-protein kinase erbb-3. Chain: a, c. Fragment: kinase domain, unp residues 698-1020. Synonym: proto-oncogene-like protein c-erbb-3, tyrosine kinase-type cell surface receptor her3. Engineered: yes. Mutation: yes. Epidermal growth factor receptor. Chain: b, d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb3, her3. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: egfr. Expression_system_taxid: 7108

Resolution:

2.98Å R-factor: 0.221 R-free: 0.267

Authors:

P.Littlefield,L.Liu,N.Jura

Key ref:

P.Littlefield et al. (2014). Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations. Sci Signal, 7, ra114. PubMed id: 25468994 DOI: 10.1126/scisignal.2005786

Date:

07-Oct-14 Release date: 10-Dec-14

Protein chains

P21860  (ERBB3_HUMAN) -  Receptor tyrosine-protein kinase erbB-3 from Homo sapiens

Seq: 1342 a.a.

Struc: 269 a.a.*

Protein chains

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

Seq: 1210 a.a.

Struc: 293 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: 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

DOI no: 10.1126/scisignal.2005786

Sci Signal 7:ra114 (2014)

PubMed id: 25468994

Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations.

P.Littlefield, L.Liu, V.Mysore, Y.Shan, D.E.Shaw, N.Jura.

ABSTRACT

The human epidermal growth factor receptor (HER) tyrosine kinases homo- and heterodimerize to activate downstream signaling pathways. HER3 is a catalytically impaired member of the HER family that contributes to the development of several human malignancies and is mutated in a subset of cancers. HER3 signaling depends on heterodimerization with a catalytically active partner, in particular epidermal growth factor receptor (EGFR) (the founding family member, also known as HER1) or HER2. The activity of homodimeric complexes of catalytically active HER family members depends on allosteric activation between the two kinase domains. To determine the structural basis for HER3 signaling through heterodimerization with a catalytically active HER family member, we solved the crystal structure of the heterodimeric complex formed by the isolated kinase domains of EGFR and HER3. The structure showed HER3 as an allosteric activator of EGFR and revealed a conserved role of the allosteric mechanism in activation of HER family members through heterodimerization. To understand the effects of cancer-associated HER3 mutations at the molecular level, we solved the structures of two kinase domains of HER3 mutants, each in a heterodimeric complex with the kinase domain of EGFR. These structures, combined with biochemical analysis and molecular dynamics simulations, indicated that the cancer-associated HER3 mutations enhanced the allosteric activator function of HER3 by redesigning local interactions at the dimerization interface.