Biology subjects

Medel-Lacruz, B.

Publications and source records attributed to Medel-Lacruz, B..

3 recordsLinked to original sources

bioRxiv2025

Integrative Biophysical Illumination of the 3D GPCRome Dynamics

Achieving high-resolution insights into protein dynamics remains a major challenge, particularly for membrane proteins such as G protein-coupled receptors (GPCRs) - a highly dynamic class of cell surface receptors and key drug targets. Here, we present an integrative strategy that bridges computational and experimental biophysical methods for probing protein dynamics. To illustrate its potential, we developed GPCRmd-NMR, a platform that synergistically combines molecular dynamics (MD) simulations with high-resolution nuclear magnetic resonance (NMR) spectroscopy across the 3D GPCRome. The resulting dataset maps over 20 billion NMR signals to more than 7 million conformational snapshots of GPCRs, enabling structure-resolved analysis at an unprecedented scale. Application across multiple GPCRs provides access to previously underexplored functional GPCR dynamics, receptor states, and sites, including microswitches and hidden ligand entrance gateways. Our integrated framework offers a powerful solution to long-standing challenges faced by both experimental and computational researchers. To support broad accessibility, GPCRmd-NMR is available as an open-access, web-based framework equipped with user-friendly analysis tools (https://www.gpcrmd.org/gpcrmd-nmr-tool) and is readily applicable to other dynamic protein families beyond GPCRs and other types of biophysical data.

bioinformatics↗

bioRxiv2024

Exploring human rare disease variants from a multidimensional perspective illuminates receptor - G protein coupling diversity

G protein-coupled receptors (GPCRs) are transmembrane proteins capable of detecting signals as diverse as odours, neurotransmitters, and hormones. Upon activation, receptor signalling converges onto four G protein subtypes to regulate intracellular responses. Therefore, variation in a single G protein gene can potentially impact the function of numerous receptors. In this work, we have performed a multidimensional study of rare disease mutations in Gs, a prototypical G protein. By integrating data from 3D structures, GPCR / G protein functional pairings, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modelling, our results reveal why mutations impairing receptor / Gs coupling result in highly specific context-based signalling defects. Furthermore, we show that mutations leading to the same rare disease can alter different signal transduction steps, highlighting the importance of patient-specific treatment strategies. By closely dissecting G protein coupling, our study provides a blueprint to interrogate GPCR pathway signalling diversity in different (patho)physiological contexts.

systems biology↗

bioRxiv2022

Single-molecule analysis of receptor-beta-arrestin interactions in living cells

{beta}-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-{beta}-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in {beta}-arrestin interactions with both receptors and the lipid bilayer. In contrast to the currently widely accepted model, we show that {beta}-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, we show that following receptor interaction, the plasma membrane stabilizes {beta}-arrestin in a membrane-bound, active-like conformation, allowing it to diffuse to clathrin coated pits separately from the activating receptor. These results challenge our current understanding of {beta}-arrestin function at the plasma membrane, revealing a new critical role for {beta}-arrestin pre-association with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.

cell biology↗