1675: Integrin Antagonist Binder Design: Round 3
|Name:||1675: Integrin Antagonist Binder Design: Round 3|
|Expired:||05/23/2019 - 23:00|
|Description:||Help design a protein binder for cancer therapy!
Integrins are cell adhesion receptors that are normally inactive on the surface of cells. Once activated by a ligand, integrins can induce changes in cell cycle, growth factor signaling pathways, cytoskeletal organization, and movement. Recently, integrins have emerged as a key target in anti-cancer therapy as integrins are involved in promoting tumor metastasis and cancer blood vessel formation. Integrin antagonists have already proven successful in halting invasion and migration of tumors.
The challenge for Foldit players is to help design a binder for the integrin binding site that will induce full antagonism.
In the previous iterations of this puzzle, we excised the binding portion of the integrin as the target. For the ligand, we froze the 9 amino acid domain where the RGD loop resides, and allowed Foldit players to design 65 residues flanking the frozen loop domain. In Round 1, Foldit players reported wiggle/shake times were too long, due to the puzzle size. In Round 2, we reduced the puzzle size and added a core-filter bonus to ensure good folds. The puzzle solutions proved to be promising!
Many of the best scoring designs made great contacts with the integrin target, but lacked a good hydrophobic core, which makes them unlikely to fold in solution. While making more contact with the target is good, hydrophobic core interaction is an important driving force in the folding of soluble protein domains. That being said, the solutions that had great cores often lacked stabilizing contact with the target outside of the loop.
As such, we've revised the objectives in this puzzle. High scoring solutions should have stable cores. Many previous solutions had too much alanine in the core, and not enough larger hydrophobic residues, so we've adjusted the score function to discourage alanine. Second, the proteins should make at least one other major contact with the target. Let’s give cancer a good fight!
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