Sandbox Reserved 430: Difference between revisions

The interaction between P2Y12 and AZD1283 is different in P2Y12 binding pocket and its PAR1 equivalent. PAR1's 24 residues of ECL2 have more interaction in ligand binding, while 16 unresolved residues ECL2 of P2Y12 is less likely to interact with AZD1283. Moreover, the shifted outward of helicies IV, VI and VII due to the extracellular make AZD1283 binds deeper into 7TM domain. It formed two pockets for the binding of AZD1283, separated by residues Y105 and K280, with pocket 1 consist of helices III-VII, while pocket 2 consists of helices I-III and VII. Among them, pocket 1 take part in the binding of AZD1283 and P2Y12, while pocket 2 does not.

The binding between P2Y12 and AZD1283 is also different from other GPCRs. The 17A elongated ligand is between helices IV and VII, which belongs in pocket 1. The antagonist AZD1283's piperidinyl-nicotinate group is inserted into sub-pocket of helices III, IV and V; while the benzylsulphonyl group interacts with helices VI and VII, forming at least seven polar and ionic interaction between P2Y12 and AZD1283.