3AT4

Crystal structure of CK2alpha with pyradine derivertive

Summary for 3AT4

• Entry DOI: 10.2210/pdb3at4/pdb
• Related: 3AT2 3AT3
• Descriptor: Casein kinase II subunit alpha, [1-(6-{6-[(1-methylethyl)amino]-1H-indazol-1-yl}pyrazin-2-yl)-1H-pyrrol-3-yl]acetic acid (3 entities in total)
• Functional Keywords: ck2, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40854.60

Authors

Kinoshita, T. (deposition date: 2010-12-23, release date: 2011-11-09, Last modification date: 2023-11-01)

Primary citation

Kinoshita, T.,Sekiguchi, Y.,Fukada, H.,Nakaniwa, T.,Tada, T.,Nakamura, S.,Kitaura, K.,Ohno, H.,Suzuki, Y.,Hirasawa, A.,Nakanishi, I.,Tsujimoto, G.
A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to CK2 kinase
Mol.Cell.Biochem., 356:97-105, 2011

PubMed Abstract: The detailed understanding of the molecular features of a ligand binding to a target protein, facilitates the successful design of potent and selective inhibitors. We present a case study of ATP-competitive kinase inhibitors that include a pyradine moiety. These compounds have similar chemical structure, except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and block kinase activity of casein kinase 2 subunit α (CK2α), which is a target for several diseases, such as cancer and glomerulonephritis. Although these compounds display similar inhibitory potency against CK2α, the crystal structures reveal that the cyclopentyl derivative gains more favorable interactions compared with the isopropyl derivative, because of the additional ethylene moiety. The structural observations and biological data are consistent with the thermodynamic profiles of these inhibitors in binding to CK2α, revealing that the enthalpic advantage of the cyclopentyl derivative is accompanied with a lower entropic loss. Computational analyses indicated that the relative enthalpic gain of the cyclopentyl derivative arises from an enhancement of a wide range of van der Waals interactions from the whole complex. Conversely, the relative entropy loss of the cyclopentyl derivative arises from a decrease in the molecular fluctuation and higher conformational restriction in the active site of CK2α. These structural insights, in combination with thermodynamic and computational observations, should be helpful in developing potent and selective CK2α inhibitors.

PubMed: 21735094
DOI: 10.1007/s11010-011-0960-9

Experimental method

X-RAY DIFFRACTION (2.2 Å)