Sandbox Reserved 430: Difference between revisions

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==Binding Interactions==

==Binding Interactions==[1]

The ~~<scene name=~~'~~48/483887/Binding_site/4'>Binding Site</scene>~~ of P2Y12 is ~~colored in purple~~, and the ~~ligand (~~AZD1283~~) is colored in yellow~~. ~~The~~ binding ~~site for~~ AZD1283, pocket 1~~, is composed~~ of helices ~~III–VII~~, while pocket ~~II contains~~ helices I-III and VII is ~~not represented here~~. The two ~~pockets~~ are ~~separated by~~ two ~~residues~~, ~~Y1053~~ and ~~K2807~~, which ~~makes~~ the ~~pocket II~~ not ~~a binding site for AZD1283. With~~ the ~~observation of~~ the AZD1283~~-bound P2Y12R with residue C97 belong to pocket 2~~, the ~~active metabolites drugs might occupy this pocket~~.

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.

C97 and C175 (two cysteine residues in helix III and ECL2 of P2Y12, respectively) are also notable in P2Y12-AZD1283 complexes. The two cysteines are highly conserved in GPCR family, and they form a disulphide bond in all GPCRs. But for P2Y12, no electron density is observed at C97, which means the disulphide bond in P2Y12 would be different. Moreover, mutation at C97 and C175 does not change the protein yield and stability, while increasing the melting temperature when in complex in AZD1283, which indicates that the mutation in both cysteine does not alter P2Y12 binding ability with AZD1283.

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@@ Line 32: / Line 32: @@
-==Binding Interactions==
+==Binding Interactions==[1]
-The <scene name='48/483887/Binding_site/4'>Binding Site</scene> of P2Y12 is colored in purple, and the ligand (AZD1283) is colored in yellow. The binding site for AZD1283, pocket 1, is composed of helices III–VII, while pocket II contains helices I-III and VII is not represented here. The two pockets are separated by two residues, Y1053 and K2807, which makes the pocket II not a binding site for AZD1283. With the observation of the AZD1283-bound P2Y12R with residue C97 belong to pocket 2, the active metabolites drugs might occupy this pocket.
+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.
+C97 and C175 (two cysteine residues in helix III and ECL2 of P2Y12, respectively) are also notable in P2Y12-AZD1283 complexes. The two cysteines are highly conserved in GPCR family, and they form a disulphide bond in all GPCRs. But for P2Y12, no electron density is observed at C97, which means the disulphide bond in P2Y12 would be different. Moreover, mutation at C97 and C175 does not change the protein yield and stability, while increasing the melting temperature when in complex in AZD1283, which indicates that the mutation in both cysteine does not alter P2Y12 binding ability with AZD1283.
 ==Additional Features==