puzzle picture
1441: Y1 Receptor Homology Modeling
Status: Closed

Summary

Name: 1441: Y1 Receptor Homology Modeling
Status: Closed
Created: 10/16/2017
Points: 100
Expired: 10/24/2017 - 23:00
Difficulty: Intermediate
Description: The neuropeptide Y receptors are a group of human cell surface receptors found in the brain and digestive system, and are involved in regulating hunger and satiety. A better understanding of the neuropeptide Y receptors could allow scientists to better understand the diseases and disorders which involve misregulation of hunger and satiety. Treatment of obesity is the obvious example, but there are other disorders characterized by a mis-regulation of hunger (such as Prader-Willi syndrome). Chemotherapy is often associated with appetite suppression, so a treatment which can increase hunger could help reduce the dangerous weight loss sometimes seen in chemotherapy patients.

In this puzzle we're asking you to model the human Y1 receptor. Currently, no structures are known for any of the neuropeptide Y receptors, but they are part of a larger class of proteins called "G-protein coupled receptors (GPCRs)". GPCRs are membrane-embedded proteins, characterized by the seven alpha helices which span the membrane. This is the largest class of proteins targeted by therapeutics. As this is a rather large protein, we're breaking the protein in the middle of the membrane, freezing the part towards the inside of the cell. We're asking you to model the part on the outside of the cell, including the ligand-binding pocket (in the middle of the helices). This portion will be critical in designing a small molecule to target Y receptors.

This is a multi-start puzzle, and we're providing you with nine different predicted structures, each based on different known structures. These have all been grafted onto the same frozen portion, so some cleanup of the long transmembrane helices at the interface between the frozen and movable sections may be needed. To access the different starting structures, use the "Reset Puzzle" option to restart from a new structure.

This puzzle is the first of a series from an academic collaboration that is hoping to develop small molecule "probe compounds" which can modulate the activity of Y receptors in the lab. Having these probe compounds can help scientists better understand these receptors and the role they play in diseases.
Categories: Overall, Prediction

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Comments

rmoretti's picture
User offline. Last seen 20 hours 38 min ago. Offline
Joined: 01/15/2010
Groups: None
Sequence information

The protein being modeled is Uniprot ID NPY1R_HUMAN.

The structures used as templates:

NinjaGreg's picture
User offline. Last seen 13 hours 12 min ago. Offline
Joined: 05/21/2010
Groups: Go Science
How to tell which you are looking at?

Did you add the name of the structure as a note somewhere?

jeff101's picture
User offline. Last seen 4 hours 25 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
Please post a chart if you figure it out:

If someone figures out which is which,
please post a chart like below about it:

(1) startingscore pdbname
(2) startingscore pdbname
....
(9) startingscore pdbname

I would guess that the sequences for each
starting structure are unique enough to
identify which starting structure goes
with which pdb.

Another idea is to tab on the 1st amino acid
and add a note there with the starting score
and structure #. Then this info should stay
in shares made from the structure.

rmoretti's picture
User offline. Last seen 20 hours 38 min ago. Offline
Joined: 01/15/2010
Groups: None
Not a direct correlation

In all cases the sequence of the starting structure is the same, and is that of the desired Y1 receptor.

Due to the size of the protein, doing the puzzle as a true alignment puzzle wouldn't work. Also, because every structure has different length loops, a direct threading approach wasn't really possible to generate these structures. Instead, these structures are derived from a short homology modeling run. (Basically, they're like server starts, but done manually instead of through a server.)

Due to the way the runs were done, there isn't necessarily a direct correlation between starting structure and input model. However, when you re-load the puzzle, a structure number should pop up. Structure 1 has all homologs contributing equally, whereas structures 2-9 each have a single structure which has more influence, those being the same order as I listed above (structure 2 is 3odu, 3 is 4djh, etc.)

Joined: 10/30/2012
Groups: Beta Folders
more time?

maybe given the size and the number of starts a little more time would be useful

Joined: 09/24/2012
Groups: Go Science
lipidic ?

Sounds like our part is in membrane. Did you change the scoring function to favour hydrophillic inside?

Joined: 06/06/2013
Groups: Gargleblasters
bonding pocket

I haven't opened the actual puzzle yet -- limited CPU has me mired in CHIKV and Aflatoxin. Apparently there are several ligands attached, at least to the first listed protein 3odu
Are those ligands included? otherwise there might be a chance we can make a total hash of the protein while scoring well

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Microsoft, Adobe, RosettaCommons