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Prediction and Targeting of Interaction Interfaces in G-protein Coupled Receptor Oligomers

[ Vol. 18 , Issue. 8 ]

Author(s):

Anke C. Schiedel, Meryem Kose, Carlos Barreto, Beatriz Bueschbell, Giulia Morra, Ozge Sensoy* and Irina S. Moreira*   Pages 714 - 746 ( 33 )

Abstract:


Background: Communication within a protein complex is mediated by physical interactions made among the protomers. Evidence for both the allosteric regulation present among the protomers of the protein oligomer and of the direct effect of membrane composition on this regulation has made it essential to investigate the underlying molecular mechanism that drives oligomerization, the type of interactions present within the complex, and to determine the identity of the interaction interface. This knowledge allows a holistic understanding of dynamics and also modulation of the function of the resulting oligomers/signalling complexes. G-Protein-Coupled Receptors (GPCRs), which are targeted by 40% of currently prescribed drugs in the market, are widely involved in the formation of such physiological oligomers/signalling complexes.

Scope: This review highlights the importance of studying Protein-Protein Interactions (PPI) by using a combination of data obtained from cutting-edge experimental and computational methods that were developed for this purpose. In particular, we focused on interaction interfaces found at GPCR oligomers as well as signalling complexes, since any problem associated with these interactions causes the onset of various crucial diseases.

Conclusion: In order to have a holistic mechanistic understanding of allosteric PPIs that drive the formation of GPCR oligomers and also to determine the composition of interaction interfaces with respect to different membrane compositions, it is essential to combine both relevant experimental and computational data. In this way, efficient and specific targeting of these interaction interfaces in oligomers/ complexes can be achieved. Thus, effective therapeutic molecules with fewer side effects can be designed to modulate the function of these physiologically important receptor family.

Keywords:

GPCRs, dimerization, PPI, oligomers, ghrelin, molecular dynamics, umbrella sampling, hot spot.

Affiliation:

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Data-driven Molecular Design, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Weill-Cornell Medical College, Department of Physiology and Biophysics, 1300 York Ave, New York, NY 10065, Istanbul Medipol University, The School of Engineering and Natural Sciences, 34810, Istanbul, Data-driven Molecular Design, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra

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