Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 34, Pages 14253-14258Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0901811106
Keywords
allostery; signal transduction; agonism; GPCR
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Funding
- National Institutes of Health [GM-048043, GM-061870]
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Allosteric regulation provides highly specific ligand recognition and signaling by transmembrane protein receptors. Unlike functions of protein molecular machines that rely on large-scale conformational transitions, signal transduction in receptors appears to be mediated by more subtle structural motions that are difficult to identify. We describe a theoretical model for allosteric regulation in receptors that addresses a fundamental riddle of signaling: What are the structural origins of the receptor agonism (specific signaling response to ligand binding)? The model suggests that different signaling pathways in bovine rhodopsin or human beta(2)-adrenergic receptor can be mediated by specific structural motions in the receptors. We discuss implications for understanding the receptor agonism, particularly the recently observed biased agonism (selected activation of specific signaling pathways), and for developing rational structure-based drug-design strategies.
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