cAMP-DEPENDENT PROTEIN KINASE CONFORMATIONAL CHANGES INDUCED BY
STAUROSPORINE AND OTHER INHIBITORS
D. Bossemeyer1, A. Girod1, V. Kinzel1,
L. Prade2, R. Huber2, R. Engh2
1Department of Pathochemistry, Deutsches
Krebsforschungzentrum, 69120, Heidelberg, Germany
2Max-Planck-Institut fuer Biochemie, Am Klopferspitz 18a,
82152 Martinsried bei Muenchen, Germany,
E-mail: engh@biochem.mpg.de
Staurosporine and isoquinoline sulfonamide
inhibitors bind to the cAMP-dependent protein kinase [1,2] with several kinds of apparent
induced fit rearrangements, including side chain rotamer adjustments, loop translations,
and general lobe or subdomain rotations. Staurosporine, for example, apparently induces a
previously unobserved domain organization distinct from the typical 'open' and 'closed'
configurations, while aromatic side chains a reorganized to optimize the binding 'box'
geometry. The isoquinoline inhibitors are associated with significant movement of the
phosphate binding loop. A detailed understanding of these rearrangements requires
distinguishing between true induced fit and effects of the crystal lattice. An
understanding of the energetics of such adjustments also among other kinases is a
prerequisite for effective modelling of new therapeutic kinase inhibitors with desired
selectivity profiles.
[1] Staurosporine-induced conformational changes of
cAMP-dependent protein kinase catalytic subunit explain inhibitory potential. L. Prade, R.
A. Engh, A. Girod, V. Kinzel, R. Huber & D. Bossemeyer, Structure 5
(1997), 1627-1637.
[2] Crystal Structure of Catalytic Subunit of cAMP-dependent Protein
Kinase in Complex with Isoquinolinesulfonyl Protein Kinase Inhibitors H7, H8, and H89, J.
Biol. Chem. 271 (1996), 26157-26164.
--
Richard Engh
Phone: (49) (89) 8578 2630
FAX: (49) (89) 8578 3516