3MA3

Crystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a naphtho-difuran ligand

3MA3 の概要

• エントリーDOI: 10.2210/pdb3ma3/pdb
• 分子名称: Proto-oncogene serine/threonine-protein kinase pim-1, Pimtide, naphtho[2,1-b:7,6-b']difuran-2,8-dicarboxylic acid, ... (4 entities in total)
• 機能のキーワード: oncogene, kinase, serine-threonine, pim1, structural genomics consortium, sgc, alternative initiation, atp-binding, manganese, membrane, metal-binding, nucleotide-binding, nucleus, phosphoprotein, proto-oncogene, serine/threonine-protein kinase, transferase, host-virus interaction, viral immunoevasion, virion, virulence, cell cycle, cell membrane
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36907.82

構造登録者

Filippakopoulos, P.,Bullock, A.,Fedorov, O.,Vollmar, M.,von Delft, F.,Cochet, C.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2010-03-23, 公開日: 2010-04-14, 最終更新日: 2024-10-16)

主引用文献

Lopez-Ramos, M.,Prudent, R.,Moucadel, V.,Sautel, C.F.,Barette, C.,Lafanechere, L.,Mouawad, L.,Grierson, D.,Schmidt, F.,Florent, J.C.,Filippakopoulos, P.,Bullock, A.N.,Knapp, S.,Reiser, J.B.,Cochet, C.
New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights.
Faseb J., 24:3171-3185, 2010

PubMed Abstract: Protein kinase casein kinase 2 (CK2) is a serine/threonine kinase with evidence of implication in growth dysregulation and apoptosis resistance, making it a relevant target for cancer therapy. Several CK2 inhibitors have been developed showing variable efficiency, emphasizing the need to expand the chemical diversity of those inhibitors. We report the identification and characterization of 2,8-difurandicarboxylic acid derivatives as a new class of nanomolar ATP-competitive inhibitors. Selectivity profiling pointed out proviral insertion Moloney virus kinases (Pim kinases) as the only other kinases that are significantly inhibited. By combining structure-activity relationship analysis with structural determination, we were able to determine the binding mode of these inhibitors for both kinases and to explain their strong inhibitory potency. Essential chemical features necessary for activity on both kinases were then identified. The described compounds are not cell permeable: however, they could provide a lead for developing novel inhibitors usable also in vivo. Given the similar but not redundant pathophysiological functions of CK2 and Pim family members, such inhibitors would provide new attractive leads for targeted cancer therapy. This work highlights that 2 functionally related kinases from different kinome branches display exquisite sensitivity to a common inhibitor.

PubMed: 20400536
DOI: 10.1096/fj.09-143743

実験手法

X-RAY DIFFRACTION (2.3 Å)