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Communication

Peptide Binding Sites of Connexin Proteins

1
Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1519 Budapest, Hungary
2
Institute of Enzymology, Research Centre for Natural Sciences, 1519 Budapest, Hungary
*
Authors to whom correspondence should be addressed.
Chemistry 2020, 2(3), 662-673; https://doi.org/10.3390/chemistry2030042
Submission received: 1 June 2020 / Revised: 26 June 2020 / Accepted: 3 July 2020 / Published: 14 July 2020
(This article belongs to the Special Issue Organic Chemistry Research in Hungary)

Abstract

Intercellular gap junction (GJ) contacts formed by the coupling of connexin (Cx) hemichannels (HCs) embedded into the plasma membranes of neighboring cells play significant role in the development, signaling and malfunctions of mammalian tissues. Understanding and targeting GJ functions, however, calls for finding valid Cx subtype-specific inhibitors. We conjecture the lack of information about binding interactions between the GJ interface forming extracellular EL1 and EL2 loops and peptide mimetics designed to specifically inhibit Cx43HC coupling to Cx43GJ. Here, we explore active spots at the GJ interface using known peptide inhibitors that mimic various segments of EL1 and EL2. Binding interactions of these peptide inhibitors and the non-peptide inhibitor quinine has been modelled in combination with the use of blind docking molecular mechanics (MM). The neuron-specific Cx36HC and astrocyte-specific Cx43HC subtypes were modelled with a template derived from the high-resolution structure of Cx26GJ. GJ-coupled and free Cx36HC and Cx43HC models were obtained by dissection of GJs (GJ-coupled) followed by 50 ns molecular dynamics (free). Molecular mechanics (MM) calculations were performed by the docking of inhibitors, explicitly the designed Cx43 EL1 or EL2 loop sequence mimetics (GAP26, P5 or P180–195, GAP27, Peptide5, respectively) and the Cx36 subtype-specific quinine into the model structures. In order to explore specific binding interactions between inhibitors and CxHC subtypes, MM/Generalized Born Surface Area (MM/GBSA) ΔGbind values for representative conformers of peptide mimetics and quinine were evaluated by mapping the binding surface of Cx36HC and Cx43HC for all inhibitors. Quinine specifically contacts Cx36 EL1 residues V54-C55-N56-T57-L58, P60 and N63. Blocking the vestibule by the side of Cx36HC entry, quinine explicitly interacts with the non-conserved V54, L58, N63 residues of Cx36 EL1. In addition, our work challenges the predicted specificity of peptide mimetics, showing that the docking site of peptides is unrelated to the location of the sequence they mimic. Binding features, such as unaffected EL2 residues and the lack of Cx43 subtype-specificity of peptide mimetics, suggest critical roles for peptide stringency and dimension, possibly pertaining to the Cx subtype-specificity of peptide inhibitors.
Keywords: connexin; gap junction; hemichannel; subtype-specific inhibitors; peptide mimetics; quinine connexin; gap junction; hemichannel; subtype-specific inhibitors; peptide mimetics; quinine

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MDPI and ACS Style

Simon, Á.; Magyar, C.; Héja, L.; Kardos, J. Peptide Binding Sites of Connexin Proteins. Chemistry 2020, 2, 662-673. https://doi.org/10.3390/chemistry2030042

AMA Style

Simon Á, Magyar C, Héja L, Kardos J. Peptide Binding Sites of Connexin Proteins. Chemistry. 2020; 2(3):662-673. https://doi.org/10.3390/chemistry2030042

Chicago/Turabian Style

Simon, Ágnes, Csaba Magyar, László Héja, and Julianna Kardos. 2020. "Peptide Binding Sites of Connexin Proteins" Chemistry 2, no. 3: 662-673. https://doi.org/10.3390/chemistry2030042

APA Style

Simon, Á., Magyar, C., Héja, L., & Kardos, J. (2020). Peptide Binding Sites of Connexin Proteins. Chemistry, 2(3), 662-673. https://doi.org/10.3390/chemistry2030042

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