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Structural signatures of DRD4 mutants revealed using molecular dynamics simulations: Implications for drug targeting

  • Nidhi Jatana
  • Lipi Thukral
  • N. Latha
Original Paper

Abstract

Human Dopamine Receptor D4 (DRD4) orchestrates several neurological functions and represents a target for many psychological disorders. Here, we examined two rare variants in DRD4; V194G and R237L, which elicit functional alterations leading to disruption of ligand binding and G protein coupling, respectively. Using atomistic molecular dynamics (MD) simulations, we provide in-depth analysis to reveal structural signatures of wild and mutant complexes with their bound agonist and antagonist ligands. We constructed intra-protein network graphs to discriminate the global conformational changes induced by mutations. The simulations also allowed us to elucidate the local side-chain dynamical variations in ligand-bound mutant receptors. The data suggest that the mutation in transmembrane V (V194G) drastically disrupts the organization of ligand binding site and causes disorder in the native helical arrangement. Interestingly, the R237L mutation leads to significant rewiring of side-chain contacts in the intracellular loop 3 (site of mutation) and also affects the distant transmembrane topology. Additionally, these mutations lead to compact ICL3 region compared to the wild type, indicating that the receptor would be inaccessible for G protein coupling. Our findings thus reveal unreported structural determinants of the mutated DRD4 receptor and provide a robust framework for design of effective novel drugs.

Keywords

GPCR Ligand binding Molecular dynamics simulations Mutations Intra-protein network 

Notes

Acknowledgments

This work was supported by funding from the Department of Biotechnology, Ministry of Science and Technology, Government of India. LT was funded by INSPIRE Faculty Fellowship from Department of Science and Technology. NJ is thankful to University Grants Commission for providing a fellowship.

Supplementary material

894_2015_2868_MOESM1_ESM.pdf (4.4 mb)
(PDF 4.44 MB)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Bioinformatics Infrastructure FacilitySri Venkateswara College (University of Delhi)New DelhiIndia
  2. 2.CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
  3. 3.CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia

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