RESEARCH: CANCER
FOLDING PROJECT #17637 PROFILE

This project looks at how RIPK2, a protein involved in cancer, interacts with other proteins. Scientists are studying how certain drugs block this interaction to understand if they can be used more effectively against cancer.

Kinases are a major target for a variety of cancer therapies, but their mechanism of action is relatively unknown at a detailed atomic level, preventing us from understanding and optimizing known inhibitors.

One example is the Serine/Threonine Kinase RIPK2.

RIPK2 inhibition is useful for cancer targeting as it prevents RIPK2 from binding a protein partner named XIAP.

In fact, there are already 3 known inhibitors that bind to RIPK2 and prevent RIPK2-XIAP binding! However, it remains difficult to optimize these ligands for clinical purposes because we do not understand how any of these three inhibitors actually act on RIPK2 to prevent XIAP binding behavior.

These four projects are simulating RIPK2 by itself and bound to each of the three inhibitors, with the hope that this will reveal a more detailed mechanism of how each inhibitor works to prevent XIAP binding.

As a bonus, this will help reveal how RIPK2 *binds* XIAP (also unknown)! In this set of projects we are studying the following systems: 16466 – RIPK2 16467 – RIPK2:CSLP43 inhibitor-bound complex 16468 – RIPK2:CSLP48 inhibitor-bound complex 16469 – RIPK2:GSK583 inhibitor-bound complex 16470 – RIPK2:WEHI-345 inhibitor-bound complex 16471 – RIPK2:BI inhibitor-bound complex 16488 – RIPK2:BI inhibitor-bound complex (alt configuration) 16489 – RIPK2:BI inhibitor-bound complex (alt configuration 2) 16490 – RIPK2:NVS inhibitor-bound complex 16491 – RIPK2 apo from the GSK bound structure 16492 – RIPK2 apo fro the BI bound structure 16493 – RIPK2 apo from a Gefitinib bound structure 16494 – RIPK2 apo from a Novartis-produced inhibitor 16495 – RIPK2:Gefitinib complex 16496 – RIPK2:Novartis inhibitor structure 17637 – RIPK2:RIPK2 dimer 17638 – RIPK2:RIPK2:XIAP trimer 17639 – RIPK2:RIPK2 XIAP:XIAP tetramer (1.2 Million atoms!).

Kinases

Enzymes that transfer phosphate groups to proteins.

Kinases are a type of enzyme that play a vital role in many cellular processes by adding phosphate groups to other molecules. This process, called phosphorylation, can activate or deactivate the target molecule, influencing its function. In cancer cells, kinases often become overactive, driving uncontrolled growth and proliferation.

RIPK2

Receptor-Interacting Protein Kinase 2

RIPK2 is a protein kinase involved in the innate immune response. It plays a crucial role in detecting pathogens and triggering inflammatory signaling pathways. Aberrant RIPK2 activity has been implicated in various autoimmune diseases and cancers.

XIAP

X-Linked Inhibitor of Apoptosis Protein

XIAP is a protein that inhibits apoptosis, or programmed cell death. It plays a vital role in preventing excessive cell death and maintaining cellular homeostasis. Cancer cells often upregulate XIAP expression to evade apoptosis and promote their survival.

Inhibitors

Molecules that block or reduce the activity of a specific target.

Inhibitors are compounds designed to interfere with the function of specific biological targets, such as enzymes or proteins. They play a crucial role in treating various diseases by blocking the activity of harmful molecules.

Ligands

Molecules that bind to a specific receptor or target.

Ligands are molecules that can bind to receptors or other targets on cells. This binding can trigger various cellular responses, such as signal transduction or gene expression. Ligands play a crucial role in drug development, where they are often used to design therapeutics.