5DH3

Crystal structure of MST2 in complex with XMU-MP-1

5DH3 の概要

• エントリーDOI: 10.2210/pdb5dh3/pdb
• 分子名称: Serine/threonine-protein kinase 3, 4-[(5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino]benzenesulfonamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: mst2, mst1, hippo pathway, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q13188
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72443.98

構造登録者

Kong, L.L.,Yun, C.H. (登録日: 2015-08-29, 公開日: 2016-08-31, 最終更新日: 2024-10-30)

主引用文献

Fan, F.,He, Z.,Kong, L.L.,Chen, Q.,Yuan, Q.,Zhang, S.,Ye, J.,Liu, H.,Sun, X.,Geng, J.,Yuan, L.,Hong, L.,Xiao, C.,Zhang, W.,Sun, X.,Li, Y.,Wang, P.,Huang, L.,Wu, X.,Ji, Z.,Wu, Q.,Xia, N.S.,Gray, N.S.,Chen, L.,Yun, C.H.,Deng, X.,Zhou, D.
Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration
Sci Transl Med, 8:352ra108-352ra108, 2016

PubMed Abstract: Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay-based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics.

PubMed: 27535619
DOI: 10.1126/scitranslmed.aaf2304

実験手法

X-RAY DIFFRACTION (2.468 Å)