5VJA
Crystal Structure of human zipper-interacting protein kinase (ZIPK, alias DAPK3) in complex with a pyrazolo[3,4-d]pyrimidinone ligand (HS38)
Summary for 5VJA
| Entry DOI | 10.2210/pdb5vja/pdb |
| Descriptor | Death-associated protein kinase 3, DIMETHYL SULFOXIDE, (2R)-2-{[1-(3-chlorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]sulfanyl}propanamide, ... (5 entities in total) |
| Functional Keywords | death-associated protein kinase 3, transferase, inhibitor, smooth muscle contraction, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 132023.38 |
| Authors | Carlson, D.A.,Singer, M.R.,Sutherland, C.,Redondo, C.,Alexander, L.,Hughes, P.F.,Knapp, S.,MacDonald, J.A.,Haystead, T.A.J. (deposition date: 2017-04-19, release date: 2018-08-08, Last modification date: 2023-10-04) |
| Primary citation | Carlson, D.A.,Singer, M.R.,Sutherland, C.,Redondo, C.,Alexander, L.T.,Hughes, P.F.,Knapp, S.,Gurley, S.B.,Sparks, M.A.,MacDonald, J.A.,Haystead, T.A.J. Targeting Pim Kinases and DAPK3 to Control Hypertension. Cell Chem Biol, 25:1195-, 2018 Cited by PubMed Abstract: Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension. In vitro and ex vivo studies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility. In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications. PubMed: 30033129DOI: 10.1016/j.chembiol.2018.06.006 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.46 Å) |
Structure validation
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