2017 March 15 - April 24
2017 May 17 - June 29
2017 BTR deadline: 04/17/17
2017 October 11 - December 21
2017 Proposal deadline: 08/01/17
2017 BTR deadline: 09/10/17
Nikola Pavletich (Memorial Sloan-Kettering Institute)
The growth of the human cell is controlled by a set of proteins that act as molecular switches. These switches are turned on or off by several other proteins and ensure that the cell grows only when appropriate. In cancer, genetic alterations often cause the deregulation of these switches and lead to the uncontrolled growth of the cell.
The Cyclin-dependent kinase proteins (CDKs) play a central role in coordinating the growth and proliferation of the eukaryotic cell. At the molecular level, CDKs act as the switches that control the cell’s progression through the cell division cycle, and also serve to process diverse growth-regulatory signals. They are turned on by the binding of Cyclin proteins and by modification through phosphorylation. They are turned off by the binding of the CIP or INK4 proteins.
At CHESS, crystallographic studies of CDKs in five different complexes have revealed the mechanisms by which these regulatory processes control the CDK switches. All of these mechanisms involve conformational changes in and around the catalytic cleft of the CDK, indicating that CDKs have evolved an intrinsic conformational flexibility. This flexibility may be central to their ability to switch states in response to a diverse range of growth-regulatory signals.
This figure shows a molecular ribbon model of how the CDK switches (blue)
are turned on by CYCLIN proteins (magenta, right) and turned off by
CKI proteins (not shown). Genetic alterations in the genes for CDKs,
CYCLINs and CKIs are among the most frequent events in cancer.