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Perspective

A Unified View of “How Allostery Works”

  • Chung-Jung Tsai mail,

    tsaic@mail.nih.gov (CJT); nussinor@helix.nih.gov (RN)

    Affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute, Center for Cancer Research, Frederick, Maryland, United States of America

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  • Ruth Nussinov mail

    tsaic@mail.nih.gov (CJT); nussinor@helix.nih.gov (RN)

    Affiliations: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute, Center for Cancer Research, Frederick, Maryland, United States of America, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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  • Published: February 06, 2014
  • DOI: 10.1371/journal.pcbi.1003394

Reader Comments (1)

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An Important Step

Posted by rlanzara on 08 Feb 2014 at 17:04 GMT


I wholeheartedly applaud and support this research. It strikes at the heart of what is germane toward understanding the ligand-receptor response. It also forces a new look at the "simpler two-state models" as being sufficiently robust to describe allostery.

Previously, we had developed a detailed and quantitative model for ligand binding and the thermodynamic free energy (see Ref. 1). Although not widely acknowledged, it seems that the present article further supports this work. However, further work (see Ref. 2) demonstrated two further important points. The first was that the quantification of the net shift is important for a specific understanding of the receptor response:

From Reference 2):

In general, two-state mathematical models have been
among the most successful for describing receptor activation
[2–8]. Most of these models calculate either the proportional or
fractional receptor occupancy as the overall receptor response
[2–5]. Although it is seductive to assume that the proportional
amount of an active receptor state should correlate with the
biological response, the experimental evidence for receptor
overexpression and spare receptors suggests that the calculation
of the net change in the active receptor state is a much better
measure for response than is the fractional or proportional
change [6–8]. This is demonstrated by the effects of agonist/
antagonist combinations on the desensitization of b-receptors
[7,8]. This is also demonstrated by receptors that are activated
by overexpression since this requires a change between R and
R* that is difficult to understand in terms of a proportional
rather than a net change [7,8].

The second important point was that biased conformational change could be accommodated by our relative simple two-state model.

From Reference 2):

These findings generally support Kenakin’s concept
of protean agonism through a mechanism that describes ligand
biased conformational change and suggest that there are multiple
ways to activate and allosterically modulate the B2AR [2,50].
This model also relates the transmembrane domain motions of
GPCRs to explicit receptor states and demonstrates that many
elements from several different models may be important parts of
a bigger view of receptor activation.

Our current work demonstrates that allosterism occurs whenever another molecule alters the "net shift", which is produced by the binding of a ligand to either or both of the two receptor states (see Ref. 3).

It is important that in order to truly quantify the events of receptor activation that the underlying chemical principle of Le Chatelier be applied to the shift in receptor states so that the net shift rather than the relative shift is used as a more complete understanding into receptor activation.

Richard G. Lanzara, MPH, Ph.D.
President and Principal Scientific Officer
Bio Balance, Inc.


References:

1) Rubenstein, LA and Lanzara, RG, Activation of G Protein-Coupled Receptors Entails Cysteine Modulation of Agonist Binding J. Molecular Structure (Theochem) 430/1-3: 57-71 (1998).

2) Rubenstein, LA, Zauhar, RJ, Lanzara, RG, Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation. Journal of Molecular Graphics and Modelling 25: 396-409 (2006).

3) Lanzara, RG, Method For Determining Drug-Molecular Combinations That Modulate And Enhance The Therapeutic Safety And Efficacy Of Biological Or Pharmaceutical Drugs. US 12/167,751 (2007).


Competing interests declared: President & Principal Scientific Officer at Bio Balance, Inc. I also have stock in Enhanced Pharmaceuticals.