8EM8

Co-crystal structure of the cGMP-dependent protein kinase PKG from Plasmodium falciparum in complex with RY-1-165

8EM8 の概要

• エントリーDOI: 10.2210/pdb8em8/pdb
• 分子名称: cGMP-dependent protein kinase, unidentified peptide fragment, [(3R)-3-{[(4M)-4-(4-cyclopropyl-2-phenyl-1H-imidazol-1-yl)pyrimidin-2-yl]amino}pyrrolidin-1-yl](1,3-thiazol-2-yl)methanone, ... (5 entities in total)
• 機能のキーワード: sgc, cgmp-kinase, inhibitor, structural genomics, structural genomics consortium, transferase
• 由来する生物種: Plasmodium falciparum (isolate 3D7); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 98630.55

構造登録者

Hutchinson, A.,Dong, A.,Seitova, A.,Bhanot, P.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2022-09-27, 公開日: 2022-11-02, 最終更新日: 2024-08-07)

主引用文献

Gilleran, J.A.,Ashraf, K.,Delvillar, M.,Eck, T.,Fondekar, R.,Miller, E.B.,Hutchinson, A.,Dong, A.,Seitova, A.,De Souza, M.L.,Augeri, D.,Halabelian, L.,Siekierka, J.,Rotella, D.P.,Gordon, J.,Childers, W.E.,Grier, M.C.,Staker, B.L.,Roberge, J.Y.,Bhanot, P.
Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.
J.Med.Chem., 67:3467-3503, 2024

PubMed Abstract: Controlling malaria requires new drugs against . The cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. sporozoites and asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

PubMed: 38372781
DOI: 10.1021/acs.jmedchem.3c01795

実験手法

X-RAY DIFFRACTION (2.54 Å)