Abstract:
:Recent crystal structures of G-protein-coupled receptors (GPCRs) have revealed ordered internal water molecules, raising questions about the functional role of those waters for receptor activation that could not be answered by the static structures. Here, we used molecular dynamics simulations to monitor--at atomic and high temporal resolution--conformational changes of central importance for the activation of three prototypical GPCRs with known crystal structures: the adenosine A2A receptor, the β2-adrenergic receptor and rhodopsin. Our simulations reveal that a hydrophobic layer of amino acid residues next to the characteristic NPxxY motif forms a gate that opens to form a continuous water channel only upon receptor activation. The highly conserved tyrosine residue Y(7.53) undergoes transitions between three distinct conformations representative of inactive, G-protein activated and GPCR metastates. Additional analysis of the available GPCR crystal structures reveals general principles governing the functional roles of internal waters in GPCRs.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Yuan S,Filipek S,Palczewski K,Vogel Hdoi
10.1038/ncomms5733subject
Has Abstractpub_date
2014-09-09 00:00:00pages
4733issn
2041-1723pii
ncomms5733journal_volume
5pub_type
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