5N3E
cAMP-dependent Protein Kinase A from Cricetulus griseus in complex with fragment like molecule 6-dimethylaminopyridine-3-carboxylic acid
Summary for 5N3E
| Entry DOI | 10.2210/pdb5n3e/pdb |
| Descriptor | cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor, 6-(dimethylamino)pyridine-3-carboxylic acid, ... (6 entities in total) |
| Functional Keywords | fragment, complex, transferase, serine threonine kinase, camp, kinase, pka |
| Biological source | Cricetulus griseus (Chinese hamster) More |
| Total number of polymer chains | 2 |
| Total formula weight | 43549.55 |
| Authors | Siefker, C.,Heine, A.,Klebe, G. (deposition date: 2017-02-08, release date: 2018-03-21, Last modification date: 2024-10-09) |
| 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., 2020 Cited by 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: 33021032DOI: 10.1002/anie.202011295 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.529 Å) |
Structure validation
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