1NQL

Structure of the extracellular domain of human epidermal growth factor (EGF) receptor in an inactive (low pH) complex with EGF.

PDB DOI: https://doi.org/10.2210/pdb1NQL/pdb

Classification: HORMONE/GROWTH FACTOR RECEPTOR
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda, Escherichia coli
Mutation(s): No

Deposited: 2003-01-21 Released: 2003-03-11
Deposition Author(s): Ferguson, K.M., Lemmon, M.A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.310
R-Value Work: 0.241
R-Value Observed: 0.247

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

This is version 2.1 of the entry. See complete history.

Literature

EGF activates its receptor by removing interactions that auto-inhibit ectodomain dimerization

Ferguson, K.M., Berger, M.B., Mendrola, J.M., Cho, H., Leahy, D.J., Lemmon, M.A.

(2003) Mol Cell 11: 507-517

PubMed: 12620237 Search on PubMed
DOI: https://doi.org/10.1016/s1097-2765(03)00047-9
Primary Citation of Related Structures:
1NQL

PubMed Abstract:
Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER) family receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation and are implicated in many human cancers. EGF activates its receptor by inducing dimerization of the 621 amino acid EGF receptor extracellular region. We describe the 2.8 A resolution crystal structure of this entire extracellular region (sEGFR) in an unactivated state. The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions. To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface. This contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists.

Organizational Affiliation

Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. [email protected]

Macromolecule Content

Total Structure Weight: 78.15 kDa
Atom Count: 5,150
Modelled Residue Count: 660
Deposited Residue Count: 677
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
epidermal growth factor receptor	A	624	Homo sapiens	Mutation(s): 0 EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00533 (Homo sapiens) Explore P00533 Go to UniProtKB: P00533
PHAROS: P00533 GTEx: ENSG00000146648
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00533
Glycosylation
Glycosylation Sites: 6	Glycosylation Focus chain A	Go to GlyGen: P00533-1
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
epidermal growth factor	B	53	Homo sapiens	Mutation(s): 0 Gene Names: EGF
UniProt & NIH Common Fund Data Resources
Find proteins for P01133 (Homo sapiens) Explore P01133 Go to UniProtKB: P01133
PHAROS: P01133 GTEx: ENSG00000138798
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P01133
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 3
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C, D	3		N-Glycosylation	Interactions Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G15407YE GlyCosmos: G15407YE GlyGen: G15407YE

Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	E	2		N-Glycosylation	Interactions Focus chain E
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A]	F [auth A], G [auth A], H [auth A], I [auth A], J [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.310
R-Value Work: 0.241
R-Value Observed: 0.247
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 119.17	α = 90
b = 103.66	β = 119.27
c = 101.49	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
MOSFLM	data reduction
CCP4	data scaling
AMoRE	phasing

Structure Validation

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Entry History

Deposition Data

Released Date: 2003-03-11

Deposition Author(s):

Ferguson, K.M.

Lemmon, M.A.

Revision History (Full details and data files)

Version 1.0: 2003-03-11
Type: Initial release
Version 1.1: 2008-04-29
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Non-polymer description, Version format compliance
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2023-08-16
Changes: Advisory, Data collection, Database references, Refinement description, Structure summary