Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference.
Combining molecular dynamics (MD) in a hydrated phospholipid (DOPC) bilayer, a Monte Carlo search, and synthesis of locked nucleotide analogues, we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y(6) receptor. 2'-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than that for the corresponding flexible 2'-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.
Costanzi
Stefano
S
NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892. USA. stefanoc@mail.nih.gov
Joshi
Bhalchandra V
BV
Maddileti
Savitri
S
Mamedova
Liaman
L
Gonzalez-Moa
Maria J
MJ
Marquez
Victor E
VE
Harden
T Kendall
TK
Jacobson
Kenneth A
KA
D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000378:metabolism
D008024:Ligands; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate