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PDBsum entry 4k9e
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Immune system
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PDB id
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4k9e
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Contents |
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221 a.a.
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220 a.a.
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193 a.a.
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PDB id:
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| Name: |
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Immune system
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Title:
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Crystal structure of kit d4d5 fragment in complex with anti-kit antibodies fab79d
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Structure:
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Light chain. Chain: l. Engineered: yes. Heavy chain. Chain: h. Engineered: yes. Mast/stem cell growth factor receptor kit. Chain: c. Synonym: scfr, piebald trait protein, pbt, proto-oncogenE C-kit,
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Source:
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Mus musculus. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606. Gene: kit, scfr. Expressed in: unidentified baculovirus.
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Resolution:
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2.70Å
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R-factor:
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0.248
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R-free:
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0.282
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Authors:
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A.V.Resheynyak,T.J.Boggon,I.Lax,J.Schlessinger
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Key ref:
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A.V.Reshetnyak
et al.
(2013).
Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.
Proc Natl Acad Sci U S A,
110,
17832-17837.
PubMed id:
DOI:
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Date:
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19-Apr-13
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Release date:
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16-Oct-13
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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Enzyme class:
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Chain C:
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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Proc Natl Acad Sci U S A
110:17832-17837
(2013)
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PubMed id:
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Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.
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A.V.Reshetnyak,
B.Nelson,
X.Shi,
T.J.Boggon,
A.Pavlenco,
E.M.Mandel-Bausch,
F.Tome,
Y.Suzuki,
S.S.Sidhu,
I.Lax,
J.Schlessinger.
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ABSTRACT
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Somatic oncogenic mutations in the receptor tyrosine kinase KIT function as
major drivers of gastrointestinal stromal tumors and a subset of acute myeloid
leukemia, melanoma, and other cancers. Although treatment of these cancers with
tyrosine kinase inhibitors shows dramatic responses and durable disease control,
drug resistance followed by clinical progression of disease eventually occurs in
virtually all patients. In this report, we describe inhibitory KIT antibodies
that bind to the membrane-proximal Ig-like D4 of KIT with significant overlap
with an epitope in D4 that mediates homotypic interactions essential for KIT
activation. Crystal structures of the anti-KIT antibody in complex with KIT D4
and D5 allowed design of affinity-matured libraries that were used to isolate
variants with increased affinity and efficacy. Isolated antibodies showed KIT
inhibition together with suppression of cell proliferation driven by
ligand-stimulated WT or constitutively activated oncogenic KIT mutant. These
antibodies represent a unique therapeutic approach and a step toward the
development of "naked" or toxin-conjugated KIT antibodies for the
treatment of KIT-driven cancers.
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