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Topic: agonist versus antagonist models  (Read 3496 times)

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Offline Babcock_Hall

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agonist versus antagonist models
« on: June 07, 2017, 07:55:13 PM »
I am involved in a project that concerns induced fit and hormone action.  One model for how agonists and antagonists work is that an agonist induces a conformational change whereas an antagonist binds but does not induce a conformational change in the receptor.  How general is this model, and are there well characterized exceptions?  In other words are there hormones or growth factors that do not induce a conformational change?  My search of the literature so far has not yielded much, although I did find one review that compared the induced fit (Koshland) to the Monod-Wyman-Changeaux model of conformational selection.  It's an interesting question in its own right, but not quite the one I am trying to address.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169905/
EDT:  This article discusses efficacy in terms of a receptor with more than one conformation:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760743/

Does anyone have any thoughts or have suggestions for books or articles that touch upon this subject?
« Last Edit: June 07, 2017, 08:12:49 PM by Babcock_Hall »

Offline Yggdrasil

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Re: agonist versus antagonist models
« Reply #1 on: June 08, 2017, 12:48:06 PM »
The answer probably depends on the exact class of receptor you are studying.

EGFR and other receptor tyrosine kinases (RTKs) show activation by dimerization rather than activation by conformational change; that is, ligand binding induces dimerization of the receptor, and dimerization leads to downstream intracellular signaling cascades.  However, dimerization brings the intracellular domains together which allows them to interact, causing a conformational change that activates the activity of the intracellular kinase domain, so conformational change is still involved.  For a detailed look at the activation mechanism of RTKs see this review from the Kuriyan group: http://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-060614-034402

WRT agonists, antagonists and conformational change, probably some of the most relevant work has been done on GPCRs.  I'd probably look up some of the recent structural work by Kobilka and Lefkowitz (e.g. https://www.nature.com/nature/journal/v535/n7612/full/nature18636.html).  I am not too familiar with this field, but I'm not sure how well tested the allosteric models are for GPCRs given the small number of structures available for these receptors.

Offline Babcock_Hall

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Re: agonist versus antagonist models
« Reply #2 on: June 12, 2017, 10:06:46 AM »
I am reviewing a paper on receptors and plan to suggest that the author(s) include certain references.

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