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

Anke C Schiedel; Meryem Kose; Carlos Barreto; Beatriz Bueschbell; Giulia Morra; Ozge Sensoy; Irina S Moreira

doi:10.2174/1568026618666180604082610

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

Curr Top Med Chem. 2018;18(8):714-746. doi: 10.2174/1568026618666180604082610.

Authors

Anke C Schiedel¹, Meryem Kose¹, Carlos Barreto², Beatriz Bueschbell¹, Giulia Morra^{3

4}, Ozge Sensoy⁵, Irina S Moreira^{2

6}

Affiliations

¹ PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
² Data-driven Molecular Design, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
³ Weill-Cornell Medical College, Department of Physiology and Biophysics, 1300 York Ave, New York, NY 10065, United States.
⁴ ICRM-CNR Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131 Milano, Italy.
⁵ Istanbul Medipol University, The School of Engineering and Natural Sciences, 34810, Istanbul, Turkey.
⁶ Bijvoet Center for Biomolecular Research, Faculty of Science - Chemistry, Utrecht University, Utrecht, 3584CH, Netherlands.

PMID: 29866008
DOI: 10.2174/1568026618666180604082610

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; PPI; dimerization; ghrelin; hot spot; molecular dynamics; oligomers; umbrella sampling..

Publication types

Review

MeSH terms

Animals
Humans
Models, Molecular
Protein Binding
Receptors, G-Protein-Coupled / antagonists & inhibitors
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / metabolism*
Software

Substances

Receptors, G-Protein-Coupled