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1664: Integrin Antagonist Binder Design: Round 2
Status: Closed


Name: 1664: Integrin Antagonist Binder Design: Round 2
Status: Closed
Created: 04/19/2019
Points: 100
Expired: 04/26/2019 - 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.

Round 2: We’re asking Foldit players to help design a complete antagonist of integrin Avb3 once more. Given the crash reports and the size of the protein in the first round, we've simplified the target to reduce wiggle and shake time. The backbone and side-chains of the target integrin are also frozen. The core RGD motif of the binder is frozen, but Foldit players can design the remaining residues into a well-folded protein!

This puzzle also includes a Core Existence Objective; designs with a significant core will receive a score bonus. See puzzle comments for Objective details.
Categories: Design, Overall

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bkoep's picture
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Residue IE Score (max +500)
Monitors that all PHE, TYR, and TRP residues are scoring well.

Core Existence (max +420+470)
Ensures that at least 25% of residues are buried in the core of the designed binder.

Residue Count (max +275)
Penalizes extra residues inserted beyond the starting 60, at a cost of 55 points per residue. Players may use up to 65 residues in total.

Joined: 05/19/2009
Groups: Contenders
Not quite accurate

The Core existence bonus seems to be at least 470, not 420 max.
The residue count at start is 51, not 60 (with 275 bonus)

Is this an error in the puzzle or the description ?

bkoep's picture
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Description error

Thanks for pointing this out! These are just problems with the description; the puzzle setup is okay.

I've corrected the max bonus for Core Existence. You're right that there are 51 designable residues. We had included the frozen loop residues when we figured the residue count of 60.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders

This puzzle has essentially the same structure as described in the notes for 1659b, only smaller, down to 307 segments from 499.

Once again, the puzzle has three protein chains, plus three ligands.

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. As bkoep explained, the ligands are manganese atoms, and it's possible they could interact with the protein.

As previously, the first chain of the protein is "integrin alpha-V", but a trimmed-down version with only 116 segments instead of 193. It still matches 6DJP and other structures in the PDB.

The B chain is likewise "integrin beta-3", but only 128 segments instead of the 243 in 1659b. Again, you'll find a partial match in a 6AVU and others in the PDB. (You may notice that 6AVU also contains the A chain.)

The third chain, the C chain, is the designable part, and has the same starting sequence found in 1659b.

This time, we're down to only two disulfide bridges:

29,42 158,165 

As before, you probably won't be able to do anything but break them, so probably best to leave them alone.

The recipe AA Edit 2.0 shows each chain and each ligand separately, making it easier to find the matching PDB entries.

frood66's picture
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regarding this 'smaller' puzzle version

It is suggested that this will be faster - it is not.

Reaction time to operations is dire.....Tho it is fair to say that crashes are less here (so far)

Truth is - this is not easily playable....I have spent some time trying....doubt I'll bother wasting much more on it tho.

I wish good luck to those with big machines.

As usual - these types of puzzles destroy the game part of this place - since only those with big machines can compete.

Sad but true.

Perhaps we can have this reposted smaller? less than 200 segs is a start. I appreciate that this puzzle is smaller in seg number than the last - but now there is an additional filter - so we're about where we were.

I (and many) want to work on this - any chance of enabling us to do so - sensibly?

LociOiling's picture
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Puzzle 1664 images It looks

Puzzle 1664 images

It looks like Bruno Kestemont had the top-scoring solution, but it failed to register here on the Foldit site.

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