6DC0

Tribbles (TRIB1) pseudokinase fused to CCAAT-enhancer binding protein (C/EBPalpha) degron

6DC0 の概要

• エントリーDOI: 10.2210/pdb6dc0/pdb
• 分子名称: Tribbles homolog 1,CCAAT/enhancer-binding protein alpha (2 entities in total)
• 機能のキーワード: tribbles, psuedokinase, ccaat-enhancer binding protein, trb1, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65618.95

構造登録者

Jamieson, S.A.,Brewster, J.L.,Mace, P.D. (登録日: 2018-05-03, 公開日: 2018-10-10, 最終更新日: 2023-10-04)

主引用文献

Jamieson, S.A.,Ruan, Z.,Burgess, A.E.,Curry, J.R.,McMillan, H.D.,Brewster, J.L.,Dunbier, A.K.,Axtman, A.D.,Kannan, N.,Mace, P.D.
Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1.
Sci Signal, 11:-, 2018

PubMed Abstract: The Tribbles family of pseudokinases recruits substrates to the ubiquitin ligase COP1 to facilitate ubiquitylation. CCAAT/enhancer-binding protein (C/EBP) family transcription factors are crucial Tribbles substrates in adipocyte and myeloid cell development. We found that the TRIB1 pseudokinase was able to recruit various C/EBP family members and that the binding of C/EBPβ was attenuated by phosphorylation. To explain the mechanism of C/EBP recruitment, we solved the crystal structure of TRIB1 in complex with C/EBPα, which revealed that TRIB1 underwent a substantial conformational change relative to its substrate-free structure and bound C/EBPα in a pseudosubstrate-like manner. Crystallographic analysis and molecular dynamics and subsequent biochemical assays showed that C/EBP binding triggered allosteric changes that link substrate recruitment to COP1 binding. These findings offer a view of pseudokinase regulation with striking parallels to bona fide kinase regulation-by means of the activation loop and αC helix-and raise the possibility of small molecules targeting either the activation "loop-in" or "loop-out" conformations of Tribbles pseudokinases.

PubMed: 30254053
DOI: 10.1126/scisignal.aau0597

実験手法

X-RAY DIFFRACTION (2.8 Å)