9D2P

PANK3 complex structure with compound PZ-4127

9D2P の概要

• エントリーDOI: 10.2210/pdb9d2p/pdb
• 分子名称: Pantothenate kinase 3, 2-(4-{2-[4-(6-chloropyridazin-3-yl)piperazin-1-yl]-2-oxoethyl}anilino)-2-oxoethyl acetate, ACETIC ACID, ... (7 entities in total)
• 機能のキーワード: pank, substrate, complex, transferase, pantothenate kinase, inhibitor, activator
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43131.25

構造登録者

Yun, M.,Lee, R.E. (登録日: 2024-08-09, 公開日: 2025-08-13, 最終更新日: 2026-04-22)

主引用文献

Coker, A.L.,Tangallapally, R.,Yun, M.K.,Subramanian, C.,Jayasinghe, T.,Miller, K.,Edwards, A.,Frank, M.,Jackowski, S.,Rock, C.O.,White, S.W.,Lee, R.E.
Discovery of Sulfonamide Pantothenate Kinase Activators and Elucidation of the Role of Isoform Selectivity in Cellular Pantothenate Kinase Activation.
J.Med.Chem., 69:6004-6013, 2026

PubMed Abstract: Coenzyme A (CoA) biosynthesis is controlled by the four isoforms of the rate-limiting enzyme pantothenate kinase (PANK), whose tissue expression and subcellular localization regulate CoA homeostasis. Pantazines are positive allosteric modulators of PANK that increase cellular CoA levels by disrupting feedback inhibition by acyl-CoA esters. In this study, a structure-guided design was used to modify the Pantazine scaffold near the ATP-binding site to address metabolic liabilities of earlier leads. Replacement of a metabolically labile cyclopropyl group with a sulfonamide introduced a new hydrogen-bonding interaction with the γ-phosphate of ATP in the PANK3•ATP•Pantazine complex. This interaction improved ligand affinity, solubility, and metabolic stability. Analysis of isoform-specific inhibition revealed that cellular CoA elevation correlates with the difference in affinity between PANK3 and PANK1β, defining an "activation window" for CoA induction. Lead sulfonamide Pantazines were metabolically stable and increased hepatic CoA levels, supporting their potential for treating metabolic CoA deficiencies.

PubMed: 41771535
DOI: 10.1021/acs.jmedchem.5c03452

実験手法

X-RAY DIFFRACTION (1.8 Å)