4IQ6

Gsk-3beta with inhibitor 6-chloro-N-cyclohexyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-amine

Summary for 4IQ6

• Entry DOI: 10.2210/pdb4iq6/pdb
• Descriptor: Glycogen synthase kinase-3 beta, 6-chloro-N-cyclohexyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-amine (2 entities in total)
• Functional Keywords: protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P49841
• Total number of polymer chains: 2
• Total formula weight: 95339.27

Authors

Tong, Y.,Stewart, K.D.,Florjancic, A.S.,Harlan, J.E.,Merta, P.J.,Przytulinska, M.,Soni, N.,Swinger, K.S.,Zhu, H.,Johnson, E.F.,Shoemaker, A.R.,Penning, T.D. (deposition date: 2013-01-10, release date: 2013-04-24, Last modification date: 2024-02-28)

Primary citation

Tong, Y.,Stewart, K.D.,Florjancic, A.S.,Harlan, J.E.,Merta, P.J.,Przytulinska, M.,Soni, N.,Swinger, K.K.,Zhu, H.,Johnson, E.F.,Shoemaker, A.R.,Penning, T.D.
Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195.
ACS Med Chem Lett, 4:211-215, 2013

PubMed Abstract: To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3β, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.

PubMed: 24900653
DOI: 10.1021/ml300348c

Experimental method

X-RAY DIFFRACTION (3.12 Å)