5BUJ

ERK2 complexed with a N-H tetrahydroazaindazole

Summary for 5BUJ

• Entry DOI: 10.2210/pdb5buj/pdb
• Related: 5BUE 5BUI
• Descriptor: Mitogen-activated protein kinase 1, 4-[3-(pyridin-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]pyridin-2(1H)-one (3 entities in total)
• Functional Keywords: erk2, mitogen-activated protein kinase 1, atp inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P28482
• Total number of polymer chains: 1
• Total formula weight: 41760.95

Authors

Bellamacina, C.R.,Shu, W.,Bussiere, D.E.,Bagdanoff, J.T. (deposition date: 2015-06-03, release date: 2015-07-15, Last modification date: 2024-03-06)

Primary citation

Bagdanoff, J.T.,Jain, R.,Han, W.,Poon, D.,Lee, P.S.,Bellamacina, C.,Lindvall, M.
Ligand efficient tetrahydro-pyrazolopyridines as inhibitors of ERK2 kinase.
Bioorg.Med.Chem.Lett., 25:3626-3629, 2015

PubMed Abstract: A series of structure based drug design hypotheses and focused screening efforts drove improvements in the potency and lipophilic efficiency of tetrahydro-pyrazolopyridine based ERK2 inhibitors. Elaboration of a fragment chemical lead established a new lipophilic aryl-Tyr interaction resulting in a substantial potency improvement. Subsequent cleavage of the lipophilic moiety led to reconfiguration of the ligand bound binding cleft. The reconfiguration established a polar contact between a newly liberated N-H and a vicinal Asp, resulting in further improvements in lipophilic efficiency and in vitro clearance.

PubMed: 26144345
DOI: 10.1016/j.bmcl.2015.06.063

Experimental method

X-RAY DIFFRACTION (1.85 Å)