RESEARCH: CANCER
FOLDING PROJECT #17638 PROFILE

This project aims to understand how drugs called inhibitors block the RIPK2 protein, which plays a role in cancer. By simulating RIPK2 and its interactions with these inhibitors, researchers hope to reveal the atomic-level mechanism of action and improve cancer treatments.

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 from high-energy molecules to substrates.

Kinases are a crucial class of enzymes involved in many cellular processes. They add phosphate groups to other molecules, acting like molecular switches to turn processes on or off. In cancer, kinases often become overactive, driving uncontrolled cell growth. Drugs targeting kinases are used to treat various cancers.

RIPK2

Receptor-interacting protein kinase 2

RIPK2 is a protein that plays a vital role in the immune system's response to infection. It helps cells detect harmful pathogens and initiate inflammatory responses. However, RIPK2 can also contribute to the development of certain cancers by promoting cell survival and growth.

XIAP

X-linked inhibitor of apoptosis protein

XIAP is a protein that prevents cell death (apoptosis). Cancer cells often overexpress XIAP to avoid dying, making it a target for cancer therapies. Inhibiting XIAP can help sensitize cancer cells to chemotherapy and other treatments.

Inhibitors

Molecules that block the activity of a specific target (e.g., enzyme or protein)

Inhibitors are drugs designed to interfere with the function of a particular molecule involved in disease. They can prevent enzymes from working, block protein interactions, or alter cellular processes.

Binding

The act of molecules coming together and attaching to each other.

Binding refers to the interaction between two molecules, where they adhere to each other through chemical forces. In drug development, binding is crucial as it allows drugs (ligands) to attach to their target proteins (receptors or enzymes) and exert their effects.

Ligands

Molecules that bind to a specific target (receptor or enzyme)

Ligands are molecules, often drugs, that can attach to specific targets in the body. They initiate various cellular responses depending on their target and binding site.