RESEARCH: CANCER
FOLDING PROJECT #16476 PROFILE

Cancer often involves many faulty proteins. This project focuses on Menin, a protein important for hormone-producing tumors. Researchers will use computer models to study how drugs block Menin and how cancer mutations affect this interaction. This could lead to better treatments for these types of cancers.

In cancer treatment it is common to target multiple different putative proteins, because multiple proteins can malfunction in tumors to drive cancer.

One such protein, particularly known to be important in endocrine gland tumors (the places where hormones are secreted), is Menin-1 (Menin).

Menin is a protein found in the nucleus protein and plays a key role in regulating cell-signaling and gene expression (which genes turn on and off).

While the explicit details of Menin's behavior are not known, targeting it's inhibition with small-molecules (ligands) has demonstrated promising potential in blocking tumor growth.

However, like with many disease, mutations within Menin can *also* counteract this ligand-binding behavior.

Therefore, it is not just important to study how Menin works, or how to target it with small molecules, but also how mutations impact Menin-Ligand interactions.

This set of projects seeks to answer the latter two questions - how do small molecules inhibit Menin and how do mutations within Menin alter small-molecule affinity.

In projects 16472 & 16473, we simulate Menin by itself and Menin bound to a known small molecule inhibitor that is shown to treat tumors in patients! Thanks to the powerhouse efforts at cataloguing cancer mutations at Memorial Sloan-Kettering, we also know of 3 mutations that impact the ability of Menin to bind this inhibitor.

Projects 16474–16483 simulate either a) each of these Menin mutants or b) Menin mutants bound to this inhibitor. Bonus: Some of these structures are being simulated with the help of the AlphaFold database!.

Menin

A protein found in the nucleus that plays a key role in regulating cell-signaling and gene expression.

Menin is a crucial protein located within the cell's nucleus. It's responsible for controlling how cells communicate with each other and which genes are turned on or off. This makes Menin vital for normal cell growth and function. In cancer, mutations in Menin can disrupt its activity, contributing to tumor development.

Ligands

Molecules that bind to a specific target (e.g., protein) and elicit a biological response.

Ligands are molecules that attach to specific targets within the body, like proteins. When they bind, they can trigger various biological effects. In drug development, ligands are often designed to interact with disease-causing proteins, aiming to treat or prevent illness.

Mutations

Permanent alterations in the DNA sequence.

Mutations are changes in the DNA code that makes up our genes. These changes can occur spontaneously or be caused by environmental factors like radiation. While some mutations are harmless, others can disrupt gene function and lead to diseases like cancer.

AlphaFold

An AI system that predicts the 3D structure of proteins from their amino acid sequence.

AlphaFold is a powerful artificial intelligence tool used to predict the shape of proteins based on their building blocks (amino acids). Understanding protein structure is crucial for drug discovery and other biological research.