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1443: Classroom Puzzle: Engineer the Active Site
Status: Closed


Name: 1443: Classroom Puzzle: Engineer the Active Site
Status: Closed
Created: 10/25/2017
Points: 100
Expired: 11/01/2017 - 23:00
Difficulty: Intermediate
Description: How enzymes catalyze reactions is still an ongoing debate in the biochemistry literature. Some people think it's most important that the active site provides the right chemical environment, others that the geometry be perfected, and others that think that the motions of the protein are most important. This puzzle is meant to allow you to try and design the active site to make the best possible enzyme. One way to improve an enzyme's activity is by binding the transition state of the reaction tighter. In this puzzle, we've put a transition-state analog into the active site, and would like you to try and improve the binding to that analog by redesigning the active site residues!

University of Denver students will be asked to read two articles alongside this Foldit puzzle. The first is a 1998 paper by Lau et al., who report computer simulations that suggest this enzyme relies on dynamic protein motions to enable the reaction. (Unfortunately this paper may not be freely available to all Foldit players.) A second, more recent, paper by Lameira et al. proposes an alternative mechanism that does not require on protein motions, but only a precisely organized active site.
Categories: Pilot

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toshiue's picture
User offline. Last seen 8 hours 59 min ago. Offline
Joined: 01/31/2016
Groups: Go Science
The two papers by Lau and Lameira

I don't have, and I imagine most don't have enough credentials to download the PDFs of those two papers. Is it possible for someone with enough credentials to DL both PDFs and post in the Forum for us to read? Thanks...

dbuske's picture
User offline. Last seen 2 years 15 weeks ago. Offline
Joined: 09/22/2011
Groups: Beta Folders

Alot of bridges with this one!
Will disulfide bridges form and fold in this puzzle?

LociOiling's picture
User offline. Last seen 9 hours 6 min ago. Offline
Joined: 12/27/2012
sorry, looks like no bridges

The puzzle has 17 cysteines, but there are also 3 mystery atoms floating around, segments 250 to 252. It looks like they're zinc atoms, held in place by nearby cysteines. (There's also a small molecule at 249.)

PDB entry 5V22 is one example of this protein. You can find it at rcsb.org. The segment numbers are different, but the amino acids are a match. It indicates the individual atoms are zincs.

In our protein, the zincs at 250 and 251 are near each other, and they've held in place by cysteines 56, 58, 73, 77, 86, 90, and 96, if I've got this right.

The zinc at 252 is held by cysteines 188, 235, 237, and 242.

So that's 11 out of 17 cysteines used up right away. The sidechains on all these cysteines are locked.

The remaining cysteines 6, 20, 28, 137, 180, and 192. These aren't near one of the zincs, but I also get "sidechain locked" when I try to move their sidechains. So I think we're out of luck on making disulfide bridges in this one, all the cysteines are for something else.

Actually, most of the segments are locked in this one, but it can be a little hard to tell. The backbone is all unlocked, and there's no way in a recipe to tell whether a sidechain is locked. If you select EnzDes coloring, the backbone of the mutatable sections shows in in a lighter color, and locked sidechains are gray. The mutatable sidechains are unlocked. It looks like all the other sidechains are locked. The mutatable segments are all near the small molecule at segment 249.

The recipe Missing Ligand 1.0.1 -- brow42 can band cases like the zinc atoms when the ligand is missing from the puzzle. Unfortunately, it does only one spot, and this puzzle has three. If you run it, select "MCys4 (4-sided die)", then pick Zn as the metal atom. It makes a nice cage of bands around the zinc at segment 250. I'm not sure the recipe covers the exact case of 250 and 251 being stabilized by 7 cysteines. I'll see if I can find what that configuration is called.

Meanwhile, the small molecule at segment 249 is the focus of the puzzle. In that way, this one is similar to the aflatoxin puzzle, 1440.

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