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Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference.

ABSTRACT: 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.

SUBMITTER: Costanzi S

PROVIDER: S-EPMC2583457 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference.

Costanzi Stefano S 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

Journal of medicinal chemistry 20051201 26

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 ext ...[more]

PMID: 16366591

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