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Structural features underlying selective inhibition of protein kinase CK2 by ATP site‐directed tetrabromo‐2‐benzotriazole
Author(s) -
Battistutta Roberto,
De Moliner Erika,
Sarno Stefania,
Zanotti Giuseppe,
Pinna Lorenzo A.
Publication year - 2001
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.19601
Subject(s) - active site , chemistry , stereochemistry , gtp' , transferase , ligand (biochemistry) , protein subunit , binding site , protein structure , enzyme , crystallography , biochemistry , receptor , gene
Two novel crystal structures of Zea mays protein kinase CK2α catalytic subunit, one in complex with the specific inhibitor 4,5,6,7‐tetrabromobenzotriazole (TBB) and another in the apo‐form, were solved at 2.2 Å resolution. These structures were compared with those of the enzyme in presence of ATP and GTP (the natural cosubstrates) and the inhibitor emodin. Interaction of TBB with the active site of CK2α is mainly due to van der Waals contacts, with the ligand fitting almost perfectly the cavity. One nitrogen of the five‐membered ring interacts with two charged residues, Glu 81 and Lys 68, in the depth of the cavity, through two water molecules. These are buried in the active site and are also generally found in the structures of CK2α enzyme analyzed so far, with the exception of the complex with emodin. In the N‐terminal lobe, the position of helix αC is particularly well preserved in all the structures examined; the Gly‐rich loop is displaced from the intermediate position it has in the apo‐form and in the presence of the natural cosubstrates (ATP/GTP) to either an upper (with TBB) or a lower position (with emodin). The selectivity of TBB for CK2 appears to be mainly dictated by the reduced size of the active site which in most other protein kinases is too large for making stable interactions with this inhibitor.