4UJA

Protein Kinase A in complex with an Inhibitor

Summary for 4UJA

• Entry DOI: 10.2210/pdb4uja/pdb
• Related: 4UJ1 4UJ2 4UJ9 4UJB
• Descriptor: CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA, PEPTIDE, 7-{(3S,4R)-4-[(5-bromothiophen-2-yl)carbonyl]pyrrolidin-3-yl}quinazolin-4(3H)-one, ... (6 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 43637.34

Authors

Alam, K.A.,Engh, R.A. (deposition date: 2015-04-09, release date: 2016-04-13, Last modification date: 2024-10-16)

Primary citation

Lauber, B.S.,Hardegger, L.A.,Asraful, A.K.,Lund, B.A.,Dumele, O.,Harder, M.,Kuhn, B.,Engh, R.A.,Diederich, F.
Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of Pka and a Pkb Mimic.
Chemistry, 22:211-, 2016

PubMed Abstract: Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi-facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-π stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach.

PubMed: 26578105
DOI: 10.1002/CHEM.201503552

Experimental method

X-RAY DIFFRACTION (1.93 Å)