6YPS

Crystal structure of the cAMP-dependent protein kinase A in complex with 4-hydroxybenzamidine

Summary for 6YPS

• Entry DOI: 10.2210/pdb6yps/pdb
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, DIMETHYL SULFOXIDE, 4-oxidanylbenzenecarboximidamide, ... (4 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: 41408.03

Authors

Oebbeke, M.,Siefker, C.,Heine, A.,Klebe, G. (deposition date: 2020-04-16, release date: 2020-12-09, Last modification date: 2024-11-13)

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 (1.35 Å)