gpcr_2

M. Madan Babu's Group

Regulatory Genomics and Systems Biology

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We are Hiring!

admin January 26, 2021 11:20 pm

We will soon be recruiting at the PhD level in the following areas: Cancer Genetics, Human Genetics, Omics, Data Science, Synthetic Biology and Molecular/Cell Biology. Watch this space for future job postings, and follow Madan on Twitter.

Current job openings:

We are always looking for talented individuals who are motivated to explore the intersection between data science and biology in a multidisciplinary and diverse working environment. The Babu Group strives to build and maintain a culture of respect, diversity, and inclusion. We strongly feel these values directly contribute to the dynamic and intellectually stimulating scientific environment we can provide.

Combinatorial expression of GPCR isoforms affects signalling and drug responses

madanm November 29, 2020 10:51 pm

G-protein-coupled receptors (GPCRs) are membrane proteins that modulate physiology across human tissues in response to extracellular signals. GPCR-mediated signalling can differ because of changes in the sequence or expression of the receptors, leading to signalling bias when comparing diverse physiological systems. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms with different patterns of expression across different tissues. Here we integrate data from human tissue-level transcriptomes, GPCR sequences and structures, proteomics, single-cell transcriptomics, population-wide genetic association studies and pharmacological experiments. We show how a single GPCR gene can diversify into several isoforms with distinct signalling properties, and how unique isoform combinations expressed in different tissues can generate distinct signalling states. Depending on their structural changes and expression patterns, some of the detected isoforms may influence cellular responses to drugs and represent new targets for developing drugs with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling that considers how combinatorial expression of isoforms in a particular cell type, tissue or organism collectively influences receptor signalling and drug responses.

The paper by Maria Marti-Solano et al can be found here

Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas

madanm January 15, 2018 9:59 pm

Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein–ligand contacts and by mapping external information. The Protein Contacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also through PDBe.

The paper by Kayikci and Venkatakrishnan et al can be found here

Pharmacogenomics of GPCR Drug Targets

madanm December 20, 2017 10:11 pm

Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients’ quality of life, and relieve the economic and societal burden due to variable drug responsiveness.

The paper by Hauser et al can be found here and the video abstract can be found here

Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

admin November 10, 2017 12:15 pm

It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identi-fied more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. 

Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.

The paper by Li et al can be found here.

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