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PDBsum entry 4krp
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Transferase/immune system
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PDB id
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4krp
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Contents |
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534 a.a.
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116 a.a.
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211 a.a.
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213 a.a.
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PDB id:
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| Name: |
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Transferase/immune system
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Title:
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Nanobody/vhh domain 9g8 in complex with the extracellular region of egfr
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Structure:
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Epidermal growth factor receptor. Chain: a. Fragment: extracellular region (unp residues 25-642). Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1. Engineered: yes. Nanobody/vhh domain 9g8. Chain: b. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Lama glama. Llama. Organism_taxid: 9844.
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Resolution:
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2.82Å
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R-factor:
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0.218
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R-free:
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0.263
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Authors:
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K.M.Ferguson,K.R.Schmitz
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Key ref:
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K.R.Schmitz
et al.
(2013).
Structural evaluation of EGFR inhibition mechanisms for nanobodies/VHH domains.
Structure,
21,
1214-1224.
PubMed id:
DOI:
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Date:
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16-May-13
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Release date:
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28-Aug-13
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PROCHECK
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Headers
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References
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P00533
(EGFR_HUMAN) -
Epidermal growth factor receptor from Homo sapiens
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Seq:
Struc:
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1210 a.a.
534 a.a.
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No UniProt id for this chain
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Enzyme class:
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Chain A:
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
Bound ligand (Het Group name = )
matches with 41.38% similarity
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Structure
21:1214-1224
(2013)
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PubMed id:
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Structural evaluation of EGFR inhibition mechanisms for nanobodies/VHH domains.
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K.R.Schmitz,
A.Bagchi,
R.C.Roovers,
P.M.van Bergen en Henegouwen,
K.M.Ferguson.
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ABSTRACT
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The epidermal growth factor receptor (EGFR) is implicated in human cancers and
is the target of several classes of therapeutic agents, including antibody-based
drugs. Here, we describe X-ray crystal structures of the extracellular region of
EGFR in complex with three inhibitory nanobodies, the variable domains of heavy
chain only antibodies (VHH). VHH domains, the smallest natural antigen-binding
modules, are readily engineered for diagnostic and therapeutic applications. All
three VHH domains prevent ligand-induced EGFR activation, but use two distinct
mechanisms. 7D12 sterically blocks ligand binding to EGFR in a manner similar to
that of cetuximab. EgA1 and 9G8 bind an epitope near the EGFR domain II/III
junction, preventing receptor conformational changes required for high-affinity
ligand binding and dimerization. This epitope is accessible to the convex VHH
paratope but inaccessible to the flatter paratope of monoclonal antibodies.
Appreciating the modes of binding and inhibition of these VHH domains will aid
in developing them for tumor imaging and/or cancer therapy.
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