Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.
Amino Acid Sequence
Animals
Baculoviridae
/ genetics
Binding Sites
Cell Adhesion Molecules
/ antagonists & inhibitors
Cell Line
Cloning, Molecular
Crystallography, X-Ray
Gene Expression
Humans
Mice
Models, Molecular
Precursor Cells, B-Lymphoid
/ cytology
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Kinase Inhibitors
/ chemistry
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
Receptor Tyrosine Kinase-like Orphan Receptors
/ antagonists & inhibitors
Receptors, Eph Family
/ antagonists & inhibitors
Recombinant Proteins
/ chemistry
Sf9 Cells
Small Molecule Libraries
/ chemistry
Spodoptera
Structural Homology, Protein
Substrate Specificity
GZD824
Wnt signaling
cancer
growth factor signaling
ponatinib
protein conformation
pseudokinases
receptor tyrosine kinases
targeted therapies
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
20
01
2020
revised:
03
05
2020
accepted:
09
06
2020
pubmed:
4
7
2020
medline:
26
8
2020
entrez:
4
7
2020
Statut:
ppublish
Résumé
Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.
Identifiants
pubmed: 32619402
pii: S1097-2765(20)30420-2
doi: 10.1016/j.molcel.2020.06.018
pmc: PMC7543951
mid: NIHMS1605742
pii:
doi:
Substances chimiques
Cell Adhesion Molecules
0
Protein Kinase Inhibitors
0
Recombinant Proteins
0
Small Molecule Libraries
0
EPHA10 protein, human
EC 2.7.10.1
EPHB6 protein, human
EC 2.7.10.1
PTK7 protein, human
EC 2.7.10.1
ROR1 protein, human
EC 2.7.10.1
ROR2 protein, human
EC 2.7.10.1
RYK protein, human
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Receptor Tyrosine Kinase-like Orphan Receptors
EC 2.7.10.1
Receptors, Eph Family
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
390-405.e7Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R35 GM122485
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA193417
Pays : United States
Organisme : National Science Foundation
ID : DGE1122492
Pays : International
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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