6TUA

The RYK Pseudokinase Domain

Summary for 6TUA

• Entry DOI: 10.2210/pdb6tua/pdb
• Descriptor: Tyrosine-protein kinase RYK, SULFATE ION (3 entities in total)
• Functional Keywords: receptor kinase pseudokinase transmembrane, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36566.99

Authors

Mathea, S.,Chatterjee, D.,Preuss, F.,Shin, D.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S. (deposition date: 2020-01-04, release date: 2020-01-15, Last modification date: 2024-01-24)

Primary citation

Sheetz, J.B.,Mathea, S.,Karvonen, H.,Malhotra, K.,Chatterjee, D.,Niininen, W.,Perttila, R.,Preuss, F.,Suresh, K.,Stayrook, S.E.,Tsutsui, Y.,Radhakrishnan, R.,Ungureanu, D.,Knapp, S.,Lemmon, M.A.
Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.
Mol.Cell, 79:390-405.e7, 2020

PubMed 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.

PubMed: 32619402
DOI: 10.1016/j.molcel.2020.06.018

Experimental method

X-RAY DIFFRACTION (2.38 Å)