5VJA

Crystal Structure of human zipper-interacting protein kinase (ZIPK, alias DAPK3) in complex with a pyrazolo[3,4-d]pyrimidinone ligand (HS38)

5VJA の概要

• エントリーDOI: 10.2210/pdb5vja/pdb
• 分子名称: 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)
• 機能のキーワード: death-associated protein kinase 3, transferase, inhibitor, smooth muscle contraction, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132023.38

構造登録者

Carlson, D.A.,Singer, M.R.,Sutherland, C.,Redondo, C.,Alexander, L.,Hughes, P.F.,Knapp, S.,MacDonald, J.A.,Haystead, T.A.J. (登録日: 2017-04-19, 公開日: 2018-08-08, 最終更新日: 2023-10-04)

主引用文献

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

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: 30033129
DOI: 10.1016/j.chembiol.2018.06.006

実験手法

X-RAY DIFFRACTION (2.46 Å)