Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

Ma, Shanshan; Chen, Yan; Dai, Antao; Yin, Wanchao; Guo, Jia; Yang, Dehua; Zhou, Fulai; Jiang, Yi; Wang, Mingwei; Xu, H. Eric

doi:10.1101/2021.06.20.449193

Cited by 4 publications

(10 citation statements)

References 73 publications

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“…This MC1R complex-model (Figure 6) revealed that the amino acid at position 13 of the ligand is likely not directly involved in contact with the MC1R (nor between human α-MSH and human MC4R). This is in agreement with recent insights from a human MC1R/α-MSH complex [25]. In addition, we assume that any variation in this position does not alter the ligand structure itself, as in high-affinity MSH subtypes (e.g., β-MSH) this position is also variable [26] as observed here in α-MSH variants of different species (Figure 2b).…”

Section: ( ) =supporting

confidence: 92%

Zebrafish Bioassay for Screening Therapeutic Candidates Based on Melanotrophic Activity

Hong

Hwang

Choi

et al. 2021

IJMS

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In this study, we used the zebrafish animal model to establish a bioassay by which physiological efficacy differential of alpha-melanocyte-stimulating hormone (α-MSH) analogues could be measured by melanosome dispersion in zebrafish larvae. Brain-skin connection research has purported the interconnectedness between the nervous system and skin physiology. Accordingly, the neuropeptide α-MSH is a key regulator in several physiological processes, such as skin pigmentation in fish. In mammals, α-MSH has been found to regulate motivated behavior, appetite, and emotion, including stimulation of satiety and anxiety. Several clinical and animal model studies of autism spectrum disorder (ASD) have already demonstrated the effectiveness of α-MSH in restoring the social deficits of autism. Therefore, we sought to analyze the effect of synthetic and naturally-occurring α-MSH variants amongst different species. Our results showed that unique α-MSH derivatives from several fish species produced differential effects on the degree of melanophore dispersion. Using α-MSH human form as a standard, we could identify derivatives that induced greater physiological effects; particularly, the synthetic analogue melanotan-II (MT-II) exhibited a higher capacity for melanophore dispersion than human α-MSH. This was consistent with previous findings in an ASD mouse model demonstrating the effectiveness of MT-II in improving ASD behavioral symptoms. Thus, the melanophore assay may serve as a useful screening tool for therapeutic candidates for novel drug discovery.

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Section: ( ) =supporting

confidence: 92%

Zebrafish Bioassay for Screening Therapeutic Candidates Based on Melanotrophic Activity

Hong

Hwang

Choi

et al. 2021

IJMS

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“…g ., angiotensin II 47,48 , bradykinin 27 , cholecystokinin-8 (CCK-8) 49 , Des-Arg 10 -kallidin 27 , gastrin-17 25 , IMV449 50 , neuromedin U 51 and neuromedin S 51 ] or the peptide middle region [ e . g ., α-melanocyte-stimulating hormone (α-MSH) 52 , arginine-vasopressin (AVP) 53 and somatostain-14 54 ], thereby achieving a significantly larger peptide-receptor interface area (>1500 Å 2 ) compared to that displayed by interaction with small molecules (<1000 Å 2 ) ( Fig. 5, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Endogenous peptides mainly bind to class A and B1 GPCRs 42,43 . Unlike its class B1 counterparts that have large extracellular domains, class A GPCRs usually adopt extended loop conformations during their insertion into the orthosteric pocket by the peptide N terminus [e.g., DAMGO 44 , C-C chemokine ligand 15 (CCL15) 28 , C-X-C motif chemokine ligand 8 (CXCL8) 45 , Aβ 42 46 , N-formyl humanin 46 and ghrelin 36 ], the peptide C terminus [e.g., angiotensin II 47,48 , bradykinin 27 , cholecystokinin-8 (CCK-8) 49 , Des-Arg 10 -kallidin 27 , gastrin-17 25 , IMV449 50 , neuromedin U 51 and neuromedin S 51 ] or the peptide middle region [e.g., α-melanocyte-stimulating hormone (α-MSH) 52 , arginine-vasopressin (AVP) 53 and somatostain-14 54 ], thereby achieving a significantly larger peptide-receptor interface area (>1500 Å 2 ) compared to that displayed by interaction with small molecules (<1000 Å 2 ) (Fig. 5, Supplementary Fig.…”

Section: Class-wide Comparisonmentioning

confidence: 99%

A unique peptide recognition mechanism by the human relaxin family peptide receptor 4 (RXFP4)

Chen

Zhou

Wang

et al. 2022

Preprint

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Members of the insulin superfamily regulate a variety of biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs), which are class A G protein-coupled receptors (GPCRs), to exert pleiotropic actions. Here, we report three cryo-electron microscopy structures of RXFP4—Gi protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053, both were discovered through medicinal chemistry efforts. The B chain of INSL5 adopts a single α-helix that penetrates into the orthostatic pocket, while the A chain sits above the orthosteric pocket to interact with the extracellular surface of RXFP4, revealing a unique peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. DC591053 selectively mimicked the action of INSL5 at RXFP4 whereas compound 4 activated both RXFP3 and RXFP4. Comparison of peptide binding modes within the insulin superfamily displayed diverse interaction mechanisms distinct to each type of the peptides. Our findings not only provide valuable insights into ligand recognition and subtype selectivity among class A GPCRs, but also expand the knowledge of signaling mechanisms in the insulin superfamily.

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“…2a). Considering its similar extracellular location with other cations in GPCRs and the relevance of cations in regulating GPCR 3,6,7,33 , we speculated that the undefined EM density map corresponds to a cation.…”

Section: Positive Allosteric Modulation Of Gpr35 By Selected Divalent...mentioning

confidence: 99%

“…Since the typical Mg 2+ and Ca 2+ coordination distances are 2.07-2.29 Å and 2.37-2.49 Å 40 , respectively, solvent water may participate in these interactions. The lacking of strong electron donors surrounding divalent cations may explain the relatively weak allosteric agonism of divalent cations to GPR35 compared to OTR, MC1R, and MC4R (10 mM vs 0.5-2 mM of effective concentrations) 6,7,38 . Together, these findings provide insights into the positive allosteric modulation of GPR35 by Mg 2+ and Ca 2+ .…”

Section: Positive Allosteric Modulation Of Gpr35 By Selected Divalent...mentioning

confidence: 99%

Insights into divalent cation regulation and G13-coupling of orphan receptor GPR35

et al. 2022

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Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes Gs, Gi/o, and Gq/11, insufficient structural evidence is accessible to understand the coupling mechanism of G12/13 protein by GPCRs. Orphan receptor GPR35, which is predominantly expressed in the gastrointestinal tract and is closely related to inflammatory bowel diseases (IBDs), stands out as a prototypical receptor for investigating ionic modulation and G13 coupling. Here we report a cryo-electron microscopy structure of G13-coupled GPR35 bound to an anti-allergic drug, lodoxamide. This structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35 and also presents a highly positively charged binding pocket and the complementary electrostatic ligand recognition mode, which explain the promiscuity of acidic ligand binding by GPR35. Structural comparison of the GPR35–G13 complex with other G protein subtypes-coupled GPCRs reveals a notable movement of the C-terminus of α5 helix of the Gα13 subunit towards the receptor core and the least outward displacement of the cytoplasmic end of GPR35 TM6. A featured ‘methionine pocket’ contributes to the G13 coupling by GPR35. Together, our findings provide a structural basis for divalent cation modulation, ligand recognition, and subsequent G13 protein coupling of GPR35 and offer a new opportunity for designing GPR35-targeted drugs for the treatment of IBDs.

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Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

Cited by 4 publications

References 73 publications

Zebrafish Bioassay for Screening Therapeutic Candidates Based on Melanotrophic Activity

Zebrafish Bioassay for Screening Therapeutic Candidates Based on Melanotrophic Activity

A unique peptide recognition mechanism by the human relaxin family peptide receptor 4 (RXFP4)

Insights into divalent cation regulation and G13-coupling of orphan receptor GPR35

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