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(Received for publication, April 22, 1996, and in revised form, July 25, 1996)
From the The discovery of several hundred different
protein kinases involved in highly diverse cellular signaling pathways
is in stark contrast to the much smaller number of known modulators of
cell signaling. Of these, the H series protein kinase inhibitors
(1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7),
N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide
(H8)
N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
(H89)) are frequently used to block signaling pathways in studies
of cellular regulation. To elucidate inhibition mechanisms at atomic
resolution and to enable structure-based drug design of potential
therapeutic modulators of signaling pathways, we determined the crystal
structures of corresponding complexes with the cAPK catalytic subunit.
Complexes with H7 and H8 (2.2 Å) and with H89 (2.3 Å) define the
binding mode of the isoquinoline-sulfonamide derivatives in the
ATP-binding site while demonstrating effects of ligand-induced
structural change. Specific interactions between the enzyme and the
inhibitors include the isoquinoline ring nitrogen ligating to backbone
amide of Val-123 and an inhibitor side chain amide bonding to the
backbone carbonyl of Glu-170. The conservation of the ATP-binding site
of protein kinases allows evaluation of factors governing general
selectivity of these inhibitors among kinases. These results should
assist efforts in the design of protein kinase inhibitors with specific
properties.
Volume 271, Number 42,
Issue of October 18, 1996
pp. 26157-26164
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
STRUCTURAL IMPLICATIONS FOR SELECTIVITY
,
and
Abteilung Strukturforschung II, Max-Planck
Institute for Biochemistry, D-82152 Martinsried and the Department for
Pathochemistry, German Cancer Research Center, D-69120 Heidelberg,
Federal Republic of Germany
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