4AGU

CRYSTAL STRUCTURE OF THE HUMAN CDKL1 KINASE DOMAIN

Summary for 4AGU

• Entry DOI: 10.2210/pdb4agu/pdb
• Descriptor: CYCLIN-DEPENDENT KINASE-LIKE 1, N-(5-{[(2S)-4-amino-2-(3-chlorophenyl)butanoyl]amino}-1H-indazol-3-yl)benzamide (3 entities in total)
• Functional Keywords: transferase, phospho-mimetic, kinase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : Q00532
• Total number of polymer chains: 3
• Total formula weight: 110264.42

Authors

Canning, P.,Sharpe, T.D.,Allerston, C.,Savitsky, P.,Pike, A.C.W.,Muniz, J.R.C.,Chaikuad, A.,Kuo, K.,Burgess-Brown, N.,Ayinampudi, V.,Zhang, Y.,Thangaratnarajah, C.,Ugochukwu, E.,Vollmar, M.,Krojer, T.,Weigelt, J.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,von Delft, F.,Knapp, S.,Bullock, A. (deposition date: 2012-01-31, release date: 2012-02-08, Last modification date: 2023-12-20)

Primary citation

Canning, P.,Park, K.,Goncalves, J.,Li, C.,Howard, C.J.,Sharpe, T.D.,Holt, L.J.,Pelletier, L.,Bullock, A.N.,Leroux, M.R.
CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function.
Cell Rep, 22:885-894, 2018

PubMed Abstract: Various kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. Here, we present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs), including an unusual ?J helix important for CDKL2 and CDKL3 activity. C. elegans CDKL-1, most closely related to CDKL1-4 and localized to neuronal cilia transition zones, modulates cilium length; this depends on its kinase activity and ?J helix-containing C terminus. Human CDKL5, linked to Rett syndrome, also localizes to cilia, and it impairs ciliogenesis when overexpressed. CDKL5 patient mutations modeled in CDKL-1 cause localization and/or cilium length defects. Together, our studies establish a disease model system suggesting cilium length defects as a pathomechanism for neurological disorders, including epilepsy.

PubMed: 29420175
DOI: 10.1016/j.celrep.2017.12.083

Experimental method

X-RAY DIFFRACTION (2.4 Å)