puzzle picture
1659b: Integrin Antagonist Binder Design
Status: Closed

Summary

Name: 1659b: Integrin Antagonist Binder Design
Status: Closed
Created: 04/08/2019
Points: 100
Expired: 04/15/2019 - 23:00
Difficulty: Advanced
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.
We’re asking Foldit players to help design a complete antagonist of integrin Avb3. The core RGD binding motif of the antagonist ligand is preserved, but the rest of the ligand is up to the Foldit players to design a well-folded protein. The loop sequence is based on a high affinity form of the wild type ligand.
In the puzzle, the target integrin heterodimer backbones are frozen, but the side chains are not. The backbone and side chains of the RGD motif loop are frozen, but players can fold and design residues on either side of the loop. Players begin with 50 designable residues.
Categories: Design, Overall

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Comments

Joined: 12/27/2012
Groups: Beta Folders
Not sure if this helps, but...

This puzzle is huge, with 499 segments at the start.

It has three protein chains, plus three ligands.

So it probably sets a record for size and complexity.

The ligands are the single-atom kind, represented as black dots. They're a little hard to see with dark background. Switching to a light background makes them easy to spot.

Chain A is segments 1 to 193. It's "integrin alpha-V", an exact match for 6DJP and other structures in the PDB.

Chain B is segments 194 to 436. It's "integrin beta-3", a close but not exact match for 6AVU and others in the PDB. The matching portion of 6AVU has four additional segments not found in the Foldit version of the protein.

Chains A and B have locked backbone, but moveable sidechains. They have no mutable segments.

Chain C is the designable part, and is segments 437 to 496 at the start. It's 60 segments with the sequence "vtprgdwne" is the middle of isoleucine. The "vtprgdwne" part is has locked backbone and sidechains. It must be the "core RGD binding motif of the antagonist ligand" mentioned in the puzzle description.

The unlocked and mutable isoleucine sections are separated from the "vtprgdwne" part by two permanent cutpoints.

The three ligands are segments 497, 498, and 499 at the start. Each ligand shows as a dot in most views, but each reports three atoms. In the "Trace Line" view, the dots become triangles. The chemical nature of the ligands can't be determined in Foldit.

Just to break up all the threes, there are *four* disulfide bridges at the start:

 
34,54 68,81 264,271 319,360

Since the backbone is locked, these bridges will tend to stay in place. You can break them manually by dragging on the sidechains. There's no disulfide bridge objective, and no possibility of any additional disulfide bridges.

Joined: 01/25/2015
Groups: Marvin's bunch
I found this by searching the

I found this by searching the sequence vtprgdwne in BLAST.
https://www.ncbi.nlm.nih.gov/Structure/pdb/4MMZ?log$=align&blast_rank=1&RID=ASFV12Z2014
dunno how helpful this would be but its interesting.

bkoep's picture
User offline. Last seen 9 hours 47 min ago. Offline
Joined: 11/15/2012
Groups: None
Thanks!

Thanks for the breakdown, LociOiling! That is all perfectly correct!

The single-atom ligands are manganese metal ions. They have a positive charge, and will prefer to interact with H-bond acceptors (especially negatively charged residues like ASP or GLU). It is not necessary for Foldit designs to interact with these metals, but they are close enough to the binding site that it may be possible.

jeff101's picture
User offline. Last seen 27 min 23 sec ago. Offline
Joined: 04/20/2012
Groups: Go Science
Is 1 week enough?

I haven't tried this puzzle yet, but it sounds large,
so I would expect it to play slowly. Will 1 week be
enough to play it effectively?

S0ckrates's picture
User offline. Last seen 4 hours 43 min ago. Offline
Joined: 05/19/2017
Groups: None
Large but not time consuming

The actual editable workspace you have is relatively tiny; it's just that the entire integrin modeled here that players have to build around is quite large. Shake and Mutate take forever though.

grogar7's picture
User offline. Last seen 1 day 13 hours ago. Offline
Joined: 10/03/2011
Unwieldy

a single iteration of shake takes over 4 minutes on my computer

Aminal88's picture
User offline. Last seen 1 hour 41 min ago. Offline
Joined: 10/29/2017
Groups: Hold My Beer
Crashing issues

Its a shame it was crashing if you wiggled everything together. Just working on the backbones worked but still a frustrating puzzle. Please test better next time before release so its no drama.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
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