6P8H

Crystal structure of CDK4 in complex with CyclinD1 and P21

6P8H の概要

• エントリーDOI: 10.2210/pdb6p8h/pdb
• 分子名称: G1/S-specific cyclin-D1, Cyclin-dependent kinase 4, Cyclin-dependent kinase inhibitor 1 (3 entities in total)
• 機能のキーワード: cyclin-dependent kinase, kinase inhibitor, cell cycle, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 71480.49

構造登録者

Guiley, K.Z.,Stevenson, J.W.,Lou, K.,Barkovich, K.J.,Bunch, K.,Tripathi, S.M.,Shokat, K.M.,Rubin, S.M. (登録日: 2019-06-07, 公開日: 2019-12-25, 最終更新日: 2023-10-11)

主引用文献

Guiley, K.Z.,Stevenson, J.W.,Lou, K.,Barkovich, K.J.,Kumarasamy, V.,Wijeratne, T.U.,Bunch, K.L.,Tripathi, S.,Knudsen, E.S.,Witkiewicz, A.K.,Shokat, K.M.,Rubin, S.M.
p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition.
Science, 366:-, 2019

PubMed Abstract: The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. Surprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib. Palbociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells. Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors.

PubMed: 31831640
DOI: 10.1126/science.aaw2106

実験手法

X-RAY DIFFRACTION (3.19 Å)