6SNX

Crystal structure of cAMP-dependent protein kinase A (CHO PKA) in complex with benzamide

Summary for 6SNX

• Entry DOI: 10.2210/pdb6snx/pdb
• Related: 6SNN
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, BENZAMIDE (3 entities in total)
• Functional Keywords: phosphotransferase, signalling pathways, glycogen metabolism, serine/threonine kinase, transferase
• Biological source: Cricetulus griseus (Chinese hamster)
• Total number of polymer chains: 1
• Total formula weight: 41356.04

Authors

Oebbeke, M.,Siefker, C.,Heine, A.,Klebe, G. (deposition date: 2019-08-27, release date: 2020-09-09, Last modification date: 2024-01-24)

Primary citation

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., 60:252-258, 2021

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

Experimental method

X-RAY DIFFRACTION (1.4 Å)