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Intermediate Overall PredictionThe 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.
The protein being modeled is Uniprot ID NPY1R_HUMAN.
The structures used as templates:
Did you add the name of the structure as a note somewhere?
maybe given the size and the number of starts a little more time would be useful
If someone figures out which is which,
please post a chart like below about it:
(1) startingscore pdbname
(2) startingscore pdbname
....
(9) startingscore pdbnameI 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.
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.)
Sounds like our part is in membrane. Did you change the scoring function to favour hydrophillic inside?
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