5N3D

cAMP-dependent Protein Kinase A from Cricetulus griseus in complex with fragment like molecule 4-(trifluoromethyl)benzenecarboximidamide

5N3D の概要

• エントリーDOI: 10.2210/pdb5n3d/pdb
• 分子名称: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha-like protein, [azanyl-[4-(trifluoromethyl)phenyl]methylidene]azanium, ... (5 entities in total)
• 機能のキーワード: fragment, complex, transferase, serine threonine kinase, camp, kinase, pka
• 由来する生物種: Cricetulus griseus (Chinese hamster); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43494.40

構造登録者

Siefker, C.,Heine, A.,Klebe, G. (登録日: 2017-02-08, 公開日: 2018-02-28, 最終更新日: 2024-10-23)

主引用文献

Oebbeke, M.,Siefker, C.,Wagner, B.,Heine, A.,Klebe, G.
Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK a Shifts Mislead Popular Bioisosterism Concepts.
Angew.Chem.Int.Ed.Engl., 2020

PubMed Abstract: Medicinal-chemistry optimization follows strategies replacing functional groups and attaching larger substituents at a promising lead scaffold. Well-established bioisosterism rules are considered, however, it is difficult to estimate whether the introduced modifications really match the required properties at a binding site. The electron density distribution and pK values are modulated influencing protonation states and bioavailability. Considering the adjacent H-bond donor/acceptor pattern of the hinge binding motif in a kinase, we studied by crystallography a set of fragments to map the required interaction pattern. Unexpectedly, benzoic acid and benzamidine, decorated with the correct substituents, are totally bioisosteric just as carboxamide and phenolic OH. A mono-dentate pyridine nitrogen out-performs bi-dentate functionalities. The importance of correctly designing pK values of attached functional groups by additional substituents at the parent scaffold is rendered prominent.

PubMed: 33021032
DOI: 10.1002/anie.202011295

実験手法

X-RAY DIFFRACTION (1.77 Å)