5OK3

Crystal Structure of the Protein-Kinase A catalytic subunit from Criteculus Griseus in complex with compounds RKp241 and Fasudil

Summary for 5OK3

• Entry DOI: 10.2210/pdb5ok3/pdb
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, UPF0418 protein FAM164A, 5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE, ... (4 entities in total)
• Functional Keywords: complex, peptidic ligand, adamantyle, transferase
• Biological source: Cricetulus griseus (Chinese hamster); More
• Total number of polymer chains: 2
• Total formula weight: 43562.48

Authors

Mueller, J.M.,Heine, A.,Klebe, G. (deposition date: 2017-07-25, release date: 2018-08-08, Last modification date: 2024-11-06)

Primary citation

Muller, J.,Kirschner, R.A.,Berndt, J.P.,Wulsdorf, T.,Metz, A.,Hrdina, R.,Schreiner, P.R.,Geyer, A.,Klebe, G.
Diamondoid Amino Acid-Based Peptide Kinase A Inhibitor Analogues.
Chemmedchem, 14:663-672, 2019

PubMed Abstract: The incorporation of diamondoid amino acids (DAAs) into peptide-like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA-containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid-phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids. Affinity and binding pose are largely conserved. One variant showed 6.5-fold potency improvement, most likely related to its increased side chain lipophilicity. A second variant exhibited slightly decreased affinity presumably due to loss of hydrogen-bond contacts to surrounding water molecules of the first solvation shell.

PubMed: 30677243
DOI: 10.1002/cmdc.201800779

Experimental method

X-RAY DIFFRACTION (1.588 Å)