Introduction
OUTLINE FOR INTRODUCTION:
A)P2Y receptors are a subunit of a catergory of purinergic G-protein-coupled receptors
Cell receptors have specificity for ATP or ADP over adenosine
P2Y12-->platelet activation and thrombus formation
Drugs Candidates - engineered molecules (allosteric regulators) that can inhibit P2Y12 receptors through conformational change and active site inhibition.
B) Plavix, Effient, and Brilinta
Effects on P2Y12
C)ADZ1283 - Binding and Pocket Chemistry
D) Differences between P2Y12r with and without ADZ1283
Note: Green Scene still to come
Overall Structure
-Secondary Structure:
The is made up of eight alpha helices. There are seven transmembrane alpha helices and a carboxy-terminal helix VII, which is parallel to the membrane bilayer.
Only one disulphide bond the amino terminus with helix VII
Helix V: straight conformation because there are no proline or glycine residues to destabilize its structure
- Polar vs nonpolar:
Polar regions are pink. Nonpolar, or hydrophobic, regions are grey.
-N to C termini:
The protein shown in displays the the N and C termini
Binding Interactions
The 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.
Additional Features
Acute coronary syndrome, a condition in which there is sudden blockage of blood flow to the heart, is majorly caused by a disease known as atherothrombosis. P2Y12 receptors are a source of anti platelet therapy for the prevention of these conditions. Clopidogrel in complex with P2Y12 in combination with aspirin has guaranteed benefits, however many of the patients treated with clopidogrel-linked P2Y12 with insufficient P2Y12-inhibition experienced inimical side effects. Drug-drug interactions, obesity, diabetes mellitus (DM), reduced left ventricular function and inflammation are all associated with inadequate response to clopidogrel therapy. Clopidogrel is a pro-drug and thienopyridine-type inhibitor of the P2Y12 receptor, which requires Cytochrome P450 to hepatic ally transform it to exert its anti platelet effect. to see this interaction between the P450 complex and Clopidogrel.
Quiz Question 1
What other residues can be used to replace the ?
See Also
Credits
Introduction - Adam Murphy
Overall Structure - Cora Ricker
Drug Binding Site - Duy Nguyen
Additional Features - Lauren Timmins
Quiz Question 1 - Aidan Finnerty
References
- ↑ Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W, Fenalti G, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature. 2014 May 1;509(7498):115-8. doi: 10.1038/nature13083. Epub 2014 Mar 23. PMID:24670650 doi:http://dx.doi.org/10.1038/nature13083
