7OAI

Crystal structure of pseudokinase CASK in complex with PFE-PKIS12

Summary for 7OAI

• Entry DOI: 10.2210/pdb7oai/pdb
• Descriptor: Peripheral plasma membrane protein CASK, 4-(Cyclopentylamino)-2-[(2,5-dichlorophenyl)methylamino]-N-[3-(2-oxo-1,3-oxazolidin-3-yl)propyl]pyrimidine-5-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: pseudokinase, kinase, inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 161230.72

Authors

Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2021-04-19, release date: 2021-05-19, Last modification date: 2024-01-31)

Primary citation

Russ, N.,Schroder, M.,Berger, B.T.,Mandel, S.,Aydogan, Y.,Mauer, S.,Pohl, C.,Drewry, D.H.,Chaikuad, A.,Muller, S.,Knapp, S.
Design and Development of a Chemical Probe for Pseudokinase Ca 2+ /calmodulin-Dependent Ser/Thr Kinase.
J.Med.Chem., 64:14358-14376, 2021

PubMed Abstract: CASK (Ca/calmodulin-dependent Ser/Thr kinase) is a member of the MAGUK (membrane-associated guanylate kinase) family that functions as neurexin kinases with roles implicated in neuronal synapses and trafficking. The lack of a canonical DFG motif, which is altered to GFG in CASK, led to the classification as a pseudokinase. However, functional studies revealed that CASK can still phosphorylate substrates in the absence of divalent metals. CASK dysfunction has been linked to many diseases, including colorectal cancer, Parkinson's disease, and X-linked mental retardation, suggesting CASK as a potential drug target. Here, we exploited structure-based design for the development of highly potent and selective CASK inhibitors based on 2,4-diaminopyrimidine-5-carboxamides targeting an unusual pocket created by the GFG motif. The presented inhibitor design offers a more general strategy for the development of pseudokinase ligands that harbor unusual sequence motifs. It also provides a first chemical probe for studying the biological roles of CASK.

PubMed: 34543009
DOI: 10.1021/acs.jmedchem.1c00845

Experimental method

X-RAY DIFFRACTION (2.3 Å)