Ligand entry pathways control the chemical space recognized by GPR183

Kjær, Viktoria Madeline Skovgaard; Stępniewski, Tomasz Maciej; Medel-Lacruz, Brian; Reinmuth, Lisa; Ciba, Marija; Rexen Ulven, Elisabeth; Bonomi, Massimiliano; Selent, Jana; Rosenkilde, Mette Marie

doi:10.1039/d2sc05962b

Cited by 3 publications

(2 citation statements)

References 53 publications

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“…The availability of experimental structures of GPR183 has provided a foundation for studying GPR183 ligands in silico . For example, molecular dynamic simulations performed by Viktoria et al have revealed that the receptor can utilize two ligand entry pathways to recognize structurally diverse ligands, offering detailed information for pocket identification and ligand design. Additionally, Li et al identified cannabidiol as a potential drug for interstitial cystitis/bladder pain syndrome by demonstrating its effective molecular binding to the GPR183 receptor .…”

Section: Discussionmentioning

confidence: 99%

Exploring the Activation Mechanism of the GPR183 Receptor

Hu,

An,

Zhang

et al. 2024

J. Phys. Chem. B

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Section: Discussionmentioning

confidence: 99%

Exploring the Activation Mechanism of the GPR183 Receptor

Hu,

An,

Zhang

et al. 2024

J. Phys. Chem. B

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“…Importantly, it is becoming increasingly clear that the pharmacological properties of ligands are determined not only by their final binding pose but to a surprisingly large degree by dynamic interactions of the ligands with the receptor along their entry path 20 , 21 , 44 , 45 . In this connection, the HCAR2 structure with its rather complex agonist entry/exit path for the orthosteric site offers clear possibilities to target this either directly or indirectly.…”

Section: Design Of Novel Hcar2 Receptor Ligands To Target Receptor Dy...mentioning

confidence: 99%

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Shenol,

Tenente,

Lückmann

et al. 2024

Nat Commun

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A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.

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Relevance of G protein‐coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation

Lopez‐Balastegui,

Stepniewski,

Kogut‐Günthel

et al. 2024

British J Pharmacology

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G protein‐coupled receptors (GPCRs) are one of the major drug targets. In recent years, computational drug design for GPCRs has mainly focused on static structures obtained through X‐ray crystallography, cryogenic electron microscopy (cryo‐EM) or in silico modelling as a starting point for virtual screening campaigns. However, GPCRs are highly flexible entities with the ability to adopt different conformational states that elicit different physiological responses. Including this knowledge in the drug discovery pipeline can help to tailor novel conformation‐specific drugs with an improved therapeutic profile. In this review, we outline our current knowledge about GPCR dynamics that is relevant for receptor activation, signalling bias and allosteric modulation. Ultimately, we highlight new technological implementations such as time‐resolved X‐ray crystallography and cryo‐EM as well as computational algorithms that can contribute to a more comprehensive understanding of receptor dynamics and its relevance for GPCR functionality.

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Ligand entry pathways control the chemical space recognized by GPR183

Abstract: The G protein-coupled receptor GPR183 utilizes two ligand entry channels: one lateral between transmembrane helices 4 and 5 facing the membrane, and one facing the extracellular environment to recognize chemically diverse ligands.

Cited by 3 publications

References 53 publications

Exploring the Activation Mechanism of the GPR183 Receptor

Exploring the Activation Mechanism of the GPR183 Receptor

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Relevance of G protein‐coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation

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