Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck)
Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals.[1][2] They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved.[3][4] The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex.[5][6] CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions.[7] Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.[6]
^Morgan D (2007). The Cell Cycle: Principles of Control. London: New Science Press Ltd. pp. 2–54, 196–266. ISBN978-0-9539181-2-6.
^Alberts B, Hopkin K, Johnson A, Morgan D, Raff M, Roberts K, Walter P (2019). Essential Cell Biology (5th ed.). W. W. Norton & Company. pp. 613–627. ISBN9780393679533.