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Writer's pictureMonserrat Avila-Zozaya

From DNA day to GPCR genomics


April is the month of DNA Day, a special day commemorating the discovery of the DNA double helix structure in 1953 and the completion of the Human Genome Project in 2003. In the United States, DNA Day was officially celebrated on April 25th, 2003. Since then, the National Human Genome Research Institute (NHGRI) has supported annual events across the country to celebrate, learn and discuss the latest advances in genomic research. Eventually, April 25th was declared and recognized as International DNA Day1.


What does DNA Day have to do with GPCRs?


The discovery of DNA's double helical structure was a scientific milestone that revolutionized molecular biology. It provided a fundamental understanding of how genetic information is stored and transferred between generations. This breakthrough also paved the way for the development of genomics, a field of study that examines an organism's entire DNA or genome, including its genes, regulatory elements, and non-coding DNA sequences. Genomics, in turn, played a crucial role in the discovery and sequencing of the beta-adrenergic receptor (βAR), the first GPCR to be identified by Robert Lefkowitz and colleagues during their study of the effects of adrenaline on cells2. This intersection of genomics and GPCR research sparked a new era of a comprehensive understanding of GPCR biology, the development of GPCR-targeted drugs, and the exploration of GPCRs as key regulators of physiological processes and therapeutic targets in medicine.


The completion of the Human Genome Project revealed that GPCR genes in the human genome range from approximately 800 to over 1,000. This variation is due to factors such as alternative splicing, gene duplications, and variability in genomic methods. However, it's worth noting that the total count of GPCR genes in the human genome is still being refined as genome sequencing technologies and bioinformatics tools improve. Also, ongoing research may discover new GPCRs or refine existing data, which could lead to adjustments in the total count of GPCR genes in the human genome. Additionally, genomic approaches such as transcriptomics and proteomics have provided insights into the expression patterns and post-translational modifications of GPCRs under different physiological conditions3.


Another significant impact of genomics on GPCR research is the elucidation of receptor structure and function. Advances in structural genomics, coupled with techniques like X-ray crystallography and cryo-electron microscopy, have allowed us to understand the structural dynamics during receptor activation. Thanks to recent scientific advances, we now have a better understanding of the structural changes that happen when a receptor is activated. For example, we know that transmembrane helices move during receptor activation and that the DRY motif plays a vital role in activating G-proteins and binding to B-arrestin4. Additionally, there have been recent discoveries of the conformational changes that occur during G-protein activation by the β2-adrenergic receptor, using a time-resolved approach5.


Furthermore, computational genomics approaches, such as structural bioinformatics analysis, have facilitated drug discovery and design targeting GPCRs, leading to the development of novel therapeutics. Advances in genomic technologies, such as genome-wide association studies and next-generation sequencing, have enabled the uncovering of associations between GPCR genetic variants and diseases. The genetic variation in GPCRs is extensive; databases like GPCRdb provide a large database of genetic variations (including single nucleotide polymorphisms or SNPs) that may impact the structure or function of GPCRs. For example over 160 SNPs have been reported for the β2AR gene, with some of these SNPs having clinical significance. Another example is the cannabinoid receptor 1 with a total of 248 SNPs, where 190 missense mutations were predicted to have a functional effect4.


Overal, genomics has been a driving force in advancing scientific knowledge and innovation within the GPCR world. The integration of genomics with structural biology, pharmacology, bioinformatics, and clinical research has opened new avenues for exploring GPCR biology, developing targeted therapies, and translating genomic discoveries into clinical practice. As we celebrate Happy DNA Day, it's a testament to how genomics has revolutionized our understanding of GPCRs and their role in human health.


References


  1. National Human Genome Research Institute, U. S. (2002) National Human Genome Research Institute. United States. https://www.genome.gov/

  2. Dixon, R. A., Kobilka, B. K., Strader, D. J., Benovic, J. L., Dohlman, H. G., Frielle, T., Bolanowski, M. A., Bennett, C. D., Rands, E., Diehl, R. E., Mumford, R. A., Slater, E. E., Sigal, I. S., Caron, M. G., Lefkowitz, R. J., & Strader, C. D. (1986). Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature, 321(6065), 75–79. https://doi.org/10.1038/321075a0

  3. Fredriksson, R., Lagerström, M. C., Lundin, L. G., & Schiöth, H. B. (2003). The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Molecular pharmacology, 63(6), 1256–1272. https://doi.org/10.1124/mol.63.6.1256

  4. Syed Haneef, S. A., & Ranganathan, S. (2019). Structural bioinformatics analysis of variants on GPCR function. Current opinion in structural biology, 55, 161–177. https://doi.org/10.1016/j.sbi.2019.04.007

  5. Papasergi-Scott, M. M., Pérez-Hernández, G., Batebi, H., Gao, Y., Eskici, G., Seven, A. B., Panova, O., Hilger, D., Casiraghi, M., He, F., Maul, L., Gmeiner, P., Kobilka, B. K., Hildebrand, P. W., & Skiniotis, G. (2023). Time-resolved cryo-EM of G protein activation by a GPCR. bioRxiv : the preprint server for biology, 2023.03.20.533387. https://doi.org/10.1101/2023.03.20.533387

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