1YDR

STRUCTURE OF CAMP-DEPENDENT PROTEIN KINASE, ALPHA-CATALYTIC SUBUNIT IN COMPLEX WITH H7 PROTEIN KINASE INHIBITOR 1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE

Summary for 1YDR

• Entry DOI: 10.2210/pdb1ydr/pdb
• Descriptor: C-AMP-DEPENDENT PROTEIN KINASE, PROTEIN KINASE INHIBITOR PEPTIDE, 1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE, ... (4 entities in total)
• Functional Keywords: complex (phosphotransferase-inhibitor), transferase, camp, phosphorylation, isoquinoline sulfonamide, serine/threonine-protein kinase, atp-binding, complex (phosphotransferase-inhibitor) complex, complex (phosphotransferase/inhibitor)
• Biological source: Bos taurus (cattle)
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 43199.14

Authors

Engh, R.A.,Girod, A.,Kinzel, V.,Huber, R.,Bossemeyer, D. (deposition date: 1996-07-24, release date: 1997-04-01, Last modification date: 2024-10-23)

Primary citation

Engh, R.A.,Girod, A.,Kinzel, V.,Huber, R.,Bossemeyer, D.
Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89. Structural implications for selectivity.
J.Biol.Chem., 271:26157-26164, 1996

PubMed Abstract: 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 A) and with H89 (2.3 A) 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.

PubMed: 8824261
DOI: 10.1074/jbc.271.42.26157

Experimental method

X-RAY DIFFRACTION (2.2 Å)