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Computationally designed GPCR quaternary structures bias signaling pathway activation

Related publications (44)

From Sequence to Dynamics to Function: Computational Design of Allostery and Ligand Selectivity in G-Protein Coupled Receptors

The phenomenon of allostery, a general property in proteins that has been heralded as "the second secret of life" remains elusive to our understanding and even more challenging to incorporate into protein design. One example of allosteric proteins with gre ...

EPFL2024

Computationally designed GPCR quaternary structures bias signaling pathway activation

Patrick Daniel Barth, Robert Everett Jefferson

Communication across membranes controls critical cellular processes and is achieved by receptors translating extracellular signals into selective cytoplasmic responses. While receptor tertiary structures can be readily characterized, receptor associations ...

2022

Computational rewiring of allosteric pathways reprograms GPCR selective responses to ligands

Patrick Daniel Barth, Mahdi Hijazi, Aurélien Laurent Jean-Charles Oggier, Dániel Kéri

G-protein-coupled receptors (GPCRs) are the largest class of cell surface receptors and drug targets, and respond to a wide variety of chemical stimuli to activate diverse cellular functions. Understanding and predicting how ligand binding triggers a speci ...

bioRxiv2022

Scaffolding protein functional sites using deep learning

Bruno Emanuel Ferreira De Sousa Correia, Karla Montserrat Castro Gilabert, Basile Isidore Martin Wicky, Jue Wang

The binding and catalytic functions of proteins are generally mediated by a small number of functional residues held in place by the overall protein structure. Here, we describe deep learning approaches for scaffolding such functional sites without needing ...

AMER ASSOC ADVANCEMENT SCIENCE2022

Reprogramming G Protein-Coupled Receptor Structure, Function And Signaling By Computational Design

Dániel Kéri

G protein-coupled receptors (GPCRs) are 7-transmembrane alpha-helical integral membrane proteins on which cells heavily rely to receive information regarding their external environment. These receptors are able to transfer information to intracellular down ...

EPFL2021

Computational design of highly signaling active membrane receptors through de novo solvent-mediated allosteric networks

Jian Wang, Patrick Daniel Barth

Protein catalysis and allostery require the atomic-level orchestration and motion of residues, ligand, solvent and protein effector molecules, but the ability to design protein activity through precise protein-solvent cooperative interactions has not been ...

2021

SPServer: split-statistical potentials for the analysis of protein structures and protein-protein interactions

Jaume Bonet Martinez

BackgroundStatistical potentials, also named knowledge-based potentials, are scoring functions derived from empirical data that can be used to evaluate the quality of protein folds and protein-protein interaction (PPI) structures. In previous works we deco ...

BMC2021

Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist

Henning Paul-Julius Stahlberg, Nicolas Calo, Polina Isaikina

The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., ...

AMER ASSOC ADVANCEMENT SCIENCE2021

Low-energy electron holography imaging of conformational variability of single-antibody molecules from electrospray ion beam deposition

Klaus Kern, Stephan Rauschenbach, Sabine Abb, Sven Alexander Szilagyi, Hannah Julia Ochner

Imaging of proteins at the single-molecule level can reveal conformational variability, which is essential for the understanding of biomolecules. To this end, a biologically relevant state of the sample must be retained during both sample preparation and i ...

NATL ACAD SCIENCES2021

The role of metal ions in G protein-coupled receptor signalling and drug discovery

Horst Vogel, Shuguang Yuan, Xueying Wang

Metal ions, such as Na+, Mg2+, Ca2+, and Zn2+, are highly abundant in biological systems. For many G protein-coupled receptors (GPCRs), metal ions, especially Na+, have been found to stabilize the receptors' inactivate state preventing receptor activation. ...

WILEY2021

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