6TU9

The ROR1 Pseudokinase Domain Bound To Ponatinib

6TU9 の概要

• エントリーDOI: 10.2210/pdb6tu9/pdb
• 分子名称: Inactive tyrosine-protein kinase transmembrane receptor ROR1, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide (3 entities in total)
• 機能のキーワード: receptor transmembrane kinase pseudokinase small-molecule inhibitor, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71962.55

構造登録者

Mathea, S.,Preuss, F.,Chatterjee, D.,Niininen, W.,Ungureanu, D.,Shin, D.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S. (登録日: 2020-01-04, 公開日: 2020-01-22, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.94 Å)