2J2I

Crystal Structure of the humab PIM1 in complex with LY333531

2J2I の概要

• エントリーDOI: 10.2210/pdb2j2i/pdb
• 関連するPDBエントリー: 1XQZ 1XR1 1XWS 1YHS 1YI3 1YI4 1YWV 1YXS 1YXT 1YXU 1YXV 1YXX 2BIK 2BIL 2BZH 2BZI 2BZJ 2BZK 2C3I
• 分子名称: PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE PIM-1, SULFATE ION, (9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21:12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIA ZACYCLOHEXADECINE-18,20-DIONE, ... (4 entities in total)
• 機能のキーワード: transferase, nucleotide-binding, alternative initiation, serine/threonine-protein kinase, atp-binding, metal-binding, proto-oncogene, kinase, cancer, leukemia, manganese, nuclear protein, proto- oncogene, phosphorylation
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36068.03

構造登録者

Debreczeni, J.E.,Bullock, A.N.,von Delft, F.,Sundstrom, M.,Arrowsmith, C.,Edwards, A.,Weigelt, J.,Knapp, S. (登録日: 2006-08-16, 公開日: 2007-02-13, 最終更新日: 2023-12-13)

主引用文献

Fedorov, O.,Marsden, B.,Pogacic, V.,Rellos, P.,Muller, S.,Bullock, A.N.,Schwaller, J.,Sundstrom, M.,Knapp, S.
A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
Proc. Natl. Acad. Sci. U.S.A., 104:20523-20528, 2007

PubMed Abstract: Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.

PubMed: 18077363
DOI: 10.1073/pnas.0708800104

実験手法

X-RAY DIFFRACTION (1.9 Å)