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

Zou, Rongfeng; Li, Shu; Chan, H.C.; Vogel, Horst; Yuan, Shuguang

doi:10.1002/wcms.1565

Cited by 15 publications

(17 citation statements)

References 92 publications

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“…In our previous work, we reported the binding modes and orthosteric/allosteric effects of various metal ions (such as Na + , Mg 2+ , Ca 2+ , and Zn 2+ ) in GPCR signaling . Being one of the most abundant ions in the body, the sodium ion deserves more attention for its related mechanism in designing new GPCR ligands.…”

Section: Discussionmentioning

confidence: 99%

Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor

Yuan

Chan

2022

J. Chem. Inf. Model.

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The allosteric modulation of G-protein-coupled receptors (GPCRs) by sodium ions has received significant attention as the crystal structures of several receptors show the binding of sodium ions (Na + ) at the conserved D 2.50 . Theoretical studies have shown that extracellular Na + would enter the allosteric D 2.50 via the orthosteric site. However, it remains unclear how the bound allosteric Na + would leave the GPCRs. In this study, we performed molecular dynamics (MD) simulations to illustrate the energy barriers of Na + transfer through the transmembrane helix bundle of β 2 AR. In contrast to the postulations from other GPCRs, the translocation of this allosteric Na + into the intracellular side is found to be significantly difficult. Hence, the translocation direction could be receptor-specific.

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Section: Discussionmentioning

confidence: 99%

Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor

Yuan

Chan

2022

J. Chem. Inf. Model.

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“…Although the relationship between the fracture mechanisms and residual membrane stresses was established, the relationship between the multi-phases of Cu x Zn y and the multivalent metal ion pairs containing Cu 3+ /Cu 2+ /Cu + and Zn 3+ /Zn 2+ /Zn + was not. These multivalent ions are crucial for the human body’s biocatalytic reactions [ 46 ]. Furthermore, Cu bonded with polyester via nitrogen (N) to form a LROP structure, which was illustrated in our previous study of structural characterization, as shown at the right of Figure 2 [ 54 ].…”

Section: Other Stimuli and Chemotherapiesmentioning

confidence: 99%

“…The second problem is the low active pharmaceutical ingredients (API)-binding affinity, resulting in a lower API cargo carrier and a lesser choice of API variations. This could be solved by the hydrophobic grafting method through metallic surface chemical modification, or MOF [ 46 ]. The third problem is the toxicity of Cu, and this could be solved by using Zn ions in CuZn to control the toxicity [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

CuZn Complex Used in Electrical Biosensors for Drug Delivery Systems

Miskon

Zaidi

2022

Materials

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This paper is to discuss the potential of using CuZn in an electrical biosensor drug carrier for drug delivery systems. CuZn is the main semiconductor ingredient that has great promise as an electrochemical detector to trigger releases of active pharmaceutical ingredients (API). This CuZn biosensor is produced with a green metal of frameworks, which is an anion node in conductive polymers linked by bioactive ligands using metal–polymerisation technology. The studies of Cu, Zn, and their oxides are highlighted by their electrochemical performance as electrical biosensors to electrically trigger API. The three main problems, which are glucose oxidisation, binding affinity, and toxicity, are highlighted, and their solutions are given. Moreover, their biocompatibilities, therapeutic efficacies, and drug delivery efficiencies are discussed with details given. Our three previous investigations of CuZn found results similar to those of other authors’ in terms of multiphases, polymerisation, and structure. This affirms that our research is on the right track, especially that related to green synthesis using plant extract, CuZn as a nanochip electric biosensor, and bioactive ligands to bind API, which are limited to the innermost circle of the non-enzymatic glucose sensor category.

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“…Bond lengths were not given, but were reportedly consistent with a magnesium coordination complex [9].…”

Section: Introductionmentioning

confidence: 99%

The μ opioid receptor crystal structure with BU72 is a covalent adduct

Munro

2022

Preprint

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Background The first crystal structure of the active μ opioid receptor (μOR) exhibited several unexplained features. The ligand BU72 exhibited many extreme deviations from ideal geometry, along with unexplained electron density around the benzylic carbon. I previously showed that inverting the benzylic configuration resolved these problems, establishing revised stereochemistry of BU72 and its analog BU74. However, another problem remains unresolved: additional unexplained electron density contacts both BU72 and a histidine residue in the N-terminus. Results Here I show that these short contacts and uninterrupted density are inconsistent with non-covalent interactions. Therefore, BU72 and μOR form a covalent adduct through an unmodeled atom, and the published model as two separate entities is incorrect. A subsequently proposed magnesium complex is also inconsistent with multiple lines of evidence. However, oxygen fits the unexplained density well. While the structure I propose is tentative, similar oxygen-bridged adducts have been reported previously in the presence of reactive oxygen species. Moreover, known sources of reactive oxygen species were present: HEPES buffer, nickel ions, and a sequence motif that forms redox-active nickel complexes. This motif contacts the unexplained density. The adduct exhibits severe strain, and the tethered N-terminus forms contacts with adjacent residues. These forces, along with the nanobody used as a G protein substitute, would be expected to influence the receptor conformation. Consistent with this, the intracellular end of the structure differs markedly from subsequent structures of active μOR bound to Gi protein. Conclusions Later Gi-bound structures are likely to be more accurate templates for docking and molecular dynamics simulations of active μOR. The possibility of reactions like this should be considered in the choice of protein truncation sites and purification conditions, and in the interpretation of excess or unexplained density.

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

Cited by 15 publications

References 92 publications

Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor

Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor

CuZn Complex Used in Electrical Biosensors for Drug Delivery Systems

The μ opioid receptor crystal structure with BU72 is a covalent adduct

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

Cited by 15 publications

References 92 publications

Translocation Mechanism of Allosteric Sodium Ions in β2-Adrenoceptor

Translocation Mechanism of Allosteric Sodium Ions in β2-Adrenoceptor

CuZn Complex Used in Electrical Biosensors for Drug Delivery Systems

The μ opioid receptor crystal structure with BU72 is a covalent adduct

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Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor

Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor