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Somatic mutations in GPCRs are implicated in cancer progression and metastasis, but mechanisms are poorly understood. Emerging evidence implicates perturbation of intra\u2010receptor activation pathway motifs whereby extracellular signals are transmitted intracellularly. Recently, sufficiently sensitive methodology was described to calculate structural strain as a function of missense mutations in AlphaFold\u2010predicted model structures, which was extensively validated on experimental and predicted structural datasets. When paired with Molecular Dynamics (MD) simulations, these tools provide a facile approach to screen mutations in silico. We applied this framework to calculate the structural and dynamic effects of cancer\u2010associated mutations in the chemokine receptor CCR3, a Class A GPCR involved in cancer and autoimmune disorders. Residue\u2010residue contact scoring refined effective strain results, highlighting significant remodeling of inter\u2010 and intra\u2010motif contacts along the highly conserved GPCR activation pathway network. We then integrated AlphaFold\u2010derived predicted Local Distance Difference Test scores with per\u2010residue Root Mean Square Fluctuations and activation pathway Contact Analysis (CONAN) from coarse grain MD simulations to identify statistically significant changes in receptor dynamics upon mutation. Finally, analysis of negative control mutants suggests false positive results in AlphaFold pipelines should be considered but can be mitigated with stricter control of statistical analysis. Our results indicate selected mutants influence structural plasticity of CCR3 related to ligand interaction, activation, and G protein coupling, using a framework that could be applicable to a wide range of biochemically relevant protein targets following further validation.<\/jats:p>","DOI":"10.1002\/pro.70013","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T14:09:05Z","timestamp":1735222145000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An in silico framework to visualize how cancer\u2010associated mutations influence structural plasticity of the chemokine receptor <scp>CCR3<\/scp>"],"prefix":"10.1002","volume":"34","author":[{"given":"Evan J.","family":"van Aalst","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas Tech University  Lubbock Texas 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