5n33 | pdb_00005n33

cAMP-dependent Protein Kinase A from Cricetulus griseus in complex with fragment like molecule 3-amino-5-(trifluoromethyl)-1H-pyridin-2-one

spinqualitylabelsall models 5n33, resolution 1.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5n33 is a 2 chain structure with sequence from Cricetulus griseus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.434Å Ligands: 8JW, DMS, MPD, SEP, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function G3HK48_CRIGR Publication Abstract from PubMed 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 pKa 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 pKa values of attached functional groups by additional substituents at the parent scaffold is rendered prominent. Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts.,Oebbeke M, Siefker C, Wagner B, Heine A, Klebe G Angew Chem Int Ed Engl. 2020 Oct 6. doi: 10.1002/anie.202011295. PMID:33021032 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also CAMP-dependent protein kinase 3D structures

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