PDBsum entry 2ahx

Cell cycle,signaling protein

PDB id: 2ahx

Contents

Protein chain

611 a.a. *

Ligands

NAG ×16

SO4 ×3

Metals

YT3

Waters ×138

* Residue conservation analysis

PDB id:

2ahx

Name:

Cell cycle,signaling protein

Title:

Crystal structure of erbb4/her4 extracellular domain

Structure:

Receptor tyrosine-protein kinase erbb-4. Chain: a, b. Fragment: extracellular domain. Synonym: p180erbb4. Tyrosine kinase-type cell surface receptor her4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb4, her4. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: hampster ovary cells.

Resolution:

2.40Å R-factor: 0.237 R-free: 0.265

Authors:

S.Bouyain,P.A.Longo,S.Li,K.M.Ferguson,D.J.Leahy

Key ref:

S.Bouyain et al. (2005). The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc Natl Acad Sci U S A, 102, 15024-15029. PubMed id: 16203964 DOI: 10.1073/pnas.0507591102

Date:

28-Jul-05 Release date: 27-Sep-05

Protein chains

Q15303  (ERBB4_HUMAN) -  Receptor tyrosine-protein kinase erbB-4 from Homo sapiens

Seq: 1308 a.a.

Struc: 611 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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⁺

L-tyrosyl-[protein] + ATP (Bound ligand (Het Group name = NAG) matches with 47.62% similarity) = O-phospho-L-tyrosyl-[protein] + ADP + H(+)

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

Added reference

DOI no: 10.1073/pnas.0507591102

Proc Natl Acad Sci U S A 102:15024-15029 (2005)

PubMed id: 16203964

The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand.

S.Bouyain, P.A.Longo, S.Li, K.M.Ferguson, D.J.Leahy.

ABSTRACT

The human ErbB family of receptor tyrosine kinases comprises the epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/Neu), ErbB3 (HER3), and ErbB4 (HER4). ErbBs play fundamental roles in cell growth and differentiation events in embryonic and adult tissues, and inappropriate ErbB activity has been implicated in several human cancers. We report here the 2.4 A crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. This structure completes the gallery of unliganded ErbB receptors and demonstrates that all human ligand-binding ErbBs adopt the autoinhibited conformation. We also show that the binding of neuregulin-1beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1. These results indicate an important role for ligand in determining pH-dependent binding and may explain different responses observed when the same ErbB receptor is stimulated by different ligands.

Selected figure(s)

Figure 2.
Fig. 2. Structure of sErbB4. (A) Ribbon diagram of sErbB4. Domains I, II, III, and IV are colored blue, green, yellow, and red, respectively. The N and C termini are indicated by the letters N and C. (B) Surface representation of sErbB4. The intramolecular contact between domains II and IV is boxed. (C) Domain II/IV contact in ligand-binding sErbBs. Residues at the tether between domains II and IV of sErbB4 are shown in green (domain II) and red (domain IV). The equivalent residues from tethered sErbB1 and sErbB3 are shown in gray and white, respectively (3, 6). The buried surface areas and the surface complementarity coefficients for each tether are indicated in the legend.

Figure 3.
Fig. 3. Comparison of ligand-binding surfaces in sErbB1 and sErbB4. (A) Conservation of sErbB1 TGF- -binding residues in sErbB4. Residues with atoms within4Åofa TGF- residue are shown in red on surface representations of sErbB1 domains I and III (4). Residues that are strictly conserved between the ErbB1 ligand-binding site and ErbB4 are colored blue on surface representations of sErbB4. (B) Electrostatic potential on the ligand-binding surfaces of ErbB1 and ErbB4. Regions with negative electrostatic potential are colored red and regions with positive electrostatic potential are colored blue (scale ± 10 e/kT).

Figures were selected by the author.