1yds

Structure of CAMP-dependent protein kinase, alpha-catalytic subunit in complex with H8 protein kinase inhibitor [N-(2-methylamino)ethyl]-5-isoquinolinesulfonamide

spinqualitylabelsall models 1yds, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1yds is a 2 chain structure with sequence from Bovin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: IQS NonStd Res: SEP, TPO Activity: Transferase, with EC number 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KAPCA_BOVIN] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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.,Engh RA, Girod A, Kinzel V, Huber R, Bossemeyer D J Biol Chem. 1996 Oct 18;271(42):26157-64. PMID:8824261 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also CAMP-dependent protein kinase 3D structures

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