Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases

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Sheetz , J B , Mathea , S , Karvonen , H , Malhotra , K , Chatterjee , D , Niininen , W , Perttilä , R , Preuss , F , Suresh , K , Stayrook , S E , Tsutsui , Y , Radhakrishnan , R , Ungureanu , D , Knapp , S & Lemmon , M A 2020 , ' Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases ' , Molecular Cell , vol. 79 , no. 3 , pp. 390-+ . https://doi.org/10.1016/j.molcel.2020.06.018

Title: Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases
Author: Sheetz, Joshua B.; Mathea, Sebastian; Karvonen, Hanna; Malhotra, Ketan; Chatterjee, Deep; Niininen, Wilhelmiina; Perttilä, Robert; Preuss, Franziska; Suresh, Krishna; Stayrook, Steven E.; Tsutsui, Yuko; Radhakrishnan, Ravi; Ungureanu, Daniela; Knapp, Stefan; Lemmon, Mark A.
Contributor organization: Genome-Scale Biology (GSB) Research Program
Research Programs Unit
University of Helsinki
Date: 2020-08-06
Language: eng
Number of pages: 23
Belongs to series: Molecular Cell
ISSN: 1097-2765
DOI: https://doi.org/10.1016/j.molcel.2020.06.018
URI: http://hdl.handle.net/10138/332879
Abstract: 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.
Subject: CRYSTAL-STRUCTURE
MYELOID-LEUKEMIA
MOLECULAR-BASIS
ABL KINASE
ROR1
BINDING
ACTIVATION
INHIBITORS
AUTOINHIBITION
MUTATION
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion


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