Nayara Braga Emídio

National Institute of Diabetes and Digestive and Kidney Diseases

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Markus Muttenthaler

University of Vienna

Priscila de Faria Pinto

Universidade Federal de Juiz de Fora

Eveline Gomes Vasconcelos

Universidade Federal de Juiz de Fora

Danielle Gomes Marconato

Universidade Federal de Juiz de Fora

Priscila Silva Grijó Farani

The University of Texas at El Paso

Werner Hoffmann

Otto-von-Guericke University Magdeburg

Leonardo Ramos Quellis

Universidade Federal de Juiz de Fora

Ross W. Cheloha

National Institute of Diabetes and Digestive and Kidney Diseases

Marcos José Marques

Universidade Federal de Alfenas

Gabriane Nascimento Porcino

Universidade de São Paulo

Cooperative Institutions

University of Queensland

Universidade Federal de Juiz de Fora

Centre National de la Recherche Scientifique

Universidade de São Paulo

Universidade Estadual de Londrina

Fundação Oswaldo Cruz

Government College University, Lahore

Universidade Federal de Minas Gerais

Research Institute for Bioscience and Biotechnology

Australian Research Council

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Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology

Molecular Pharmacology (2023)

Nayara Braga Emídio Brandi M. Small Amanda R. Keller Ross W. Cheloha Laura M. Wingler

Dualsteric G protein-coupled receptor (GPCR) ligands are a class of bitopic ligands that consist of an orthosteric pharmacophore, which binds to the pocket occupied by the receptor's endogenous agonist, and an allosteric pharmacophore, which binds to a distinct site. These ligands have the potential to display characteristics of both orthosteric and allosteric ligands. To explore the signaling profiles that dualsteric ligands of the angiotensin II type 1 receptor (AT1R) can access, we ligated a 6e epitope tag-specific nanobody (single-domain antibody fragment) to angiotensin II (AngII) and analogs that show preferential allosteric coupling to Gq (TRV055, TRV056) or β-arrestin (TRV027). While the nanobody itself acts as a probe-specific neutral or negative allosteric ligand of N-terminally 6e-tagged AT1R, nanobody conjugation to orthosteric ligands had varying effects on Gq dissociation and β-arrestin plasma membrane recruitment. The potency of certain AngII analogs was enhanced up to 100-fold, and some conjugates behaved as partial agonists, with up to a 5-fold decrease in maximal efficacy. Nanobody conjugation also biased the signaling of TRV055 and TRV056 toward Gq, suggesting that Gq bias at AT1R can be modulated through molecular mechanisms distinct from those previously elucidated. Both competition radioligand binding experiments and functional assays demonstrated that orthosteric antagonists (angiotensin receptor blockers) act as non-competitive inhibitors of all these nanobody-peptide conjugates. This proof-of-principle study illustrates the array of pharmacological patterns that can be achieved by incorporating neutral or negative allosteric pharmacophores into dualsteric ligands. Nanobodies directed toward linear epitopes could provide a rich source of allosteric reagents for this purpose.

SIGNIFICANCE STATEMENT

Here we engineer bitopic (dualsteric) ligands for epitope-tagged angiotensin II type 1 receptor by conjugating angiotensin II or its biased analogs to an epitope-specific nanobody (antibody fragment). Our data demonstrate that nanobody-mediated interactions with the receptor N-terminus endow angiotensin analogs with properties of allosteric modulators and provide a novel mechanism to increase the potency, modulate the maximal effect, or alter the bias of ligands.

Allosteric modulator

Radioligand

10.1124/molpharm.123.000797

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Citations (4)

The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions

International Journal of Molecular Sciences (2020)

Jörn Heuer Franziska Heuer René Stürmer Sönke Harder Hartmut Schlüter

TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).

10.3390/ijms21072508

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Citations (31)

Purificação da nucleosídeo trifosfato difosfohidrolase 1 (NTPDase 1) antigênica de Leishmania infantum

Principia Caminhos da Iniciação Científica (2020)

Ana Carolina Ribeiro Gomes Maia Michelle de Lima Detoni Leonardo Ramos Quellis Gabriane Nascimento Porcino Danielle Gomes Marconato

As NTPDases (nucleosídeo trifosfato difosfohidrolases) são enzimas que hidrolisam nucleosídeos di- e trifosfatados sob ativação de íons bivalentes. Uma atividade NTPDásica foi caracterizada em promastigotas de Leishmania infantum, um protozoário causador de leishmaniose visceral.Neste trabalho, a NTPDase 1 foi purificada de preparação de promastigotas usando como estratégia eletroforese em gel não-desnaturante e os detergentes deoxicolato de sódio e Triton X-100, os quais preservam a atividade fosfohidrolítica desta enzima. Após eletroforese, incubação do gel com ATP e inibidor de ATPases do tipo P permitiu a visualização de uma única banda com depósito branco de fosfato de cálcio. Esta banda ativa foi isolada e por SDS-PAGE e coloração pela prata foi identificada como polipeptídeos de 50 e 47 kDa. Por Western blot, os dois polipeptídeos foram reconhecidos pelo soro imune anti-LbB1LJ, o qual reconhece especificamente a porção N-terminal do domínio B de NTPDases 1 de Leishmania. Por espectrometria de massas, a identidade da NTPDase 1 foi confirmada pela identificação de seis peptídeos trípticos coincidentes com a NTPDase 1 anotada em seu genoma (NCBI gi|134068433), uma cobertura de 19% de sua sequência primária. As atividades ATPásica (555 ± 93 nmol Pi x mg-1 x min-1) e ADPásica (644 ± 38 nmol Pi x mg-1 x min-1) revelaram um índice de purificação de aproximadamente 62 vezes e uma razão de atividade ATPase/ADPase de aproximadamente 1, confirmando a efetividade desta estratégia para o isolamento da NTPDase 1 de promastigotas de L. infantum.

10.34019/2179-3700.2018.v18.29857

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Identification of a linear IgE inducing epitope on the SmATPDase1 surface

Acta Biochimica et Biophysica Sinica (2017)

Nayara Braga Emídio Michélia Antônia do Nascimento Gusmão William C. Borges Clóvis R. Nakaie Eveline Gomes Vasconcelos

Identification

Linear epitope

10.1093/abbs/gmx031

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Potato apyrase reduces granulomatous area and increases presence of multinucleated giant cells in murine schistosomiasis

Parasitology International (2021)

Michélia A. N. Gusmão Sérgio Mendanha Júnior Danielle Gomes Marconato Nayara Braga Emídio Priscila Silva Grijó Farani

Apyrase

10.1016/j.parint.2021.102317

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Citations (6)

Academic publishing requires linguistically inclusive policies

Henry Arenas‐Castro Violeta Berdejo‐Espinola Shawan Chowdhury Argelia Rodríguez‐Contreras Aubrie R. M. James

Scientific knowledge is produced in multiple languages but is predominantly published in English. This academic publishing practice creates a language barrier to the generation and transfer of scientific knowledge between communities with diverse linguistic backgrounds, hindering the ability of scholars and communities to address global challenges and achieve diversity and equity in science, technology, engineering, and mathematics (STEM). To overcome those barriers, publishers and journals should provide a fair system that supports non-native English speakers and disseminates knowledge across the globe. We surveyed policies of 736 journals in biological sciences to assess their linguistic inclusivity, identify predictors of inclusivity, and propose actions to overcome language barriers in academic publishing.

Globe

Linguistic Diversity

Equity

10.32942/x2ns3k

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Citations (10)

Molecular profiling of the Mahanarva spectabilis salivary glands and phytohormonal response of elephant grass

International Journal of Tropical Insect Science (2020)

Nayara B. Saraiva Nayara Braga Emídio Camilo Elber Vital Michélia A. N. Gusmão Danielle Gomes Marconato

Jasmonic acid

Brown planthopper

10.1007/s42690-020-00275-9

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Contributors

Elsevier eBooks (2021)

R. Abhishek Biswal Şevki Adem Ahmad Adnan Nafees Ahemad Hammad Ahmed

10.1016/b978-0-12-822923-1.09993-3

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Screening of plant derived chalcones on the inhibition of potato apyrase: Potential protein biotechnological applications in health

International Journal of Biological Macromolecules (2020)

Priscila Silva Grijó Farani Danielle Gomes Marconato Nayara Braga Emídio Vinícius R. D. Pereira Ismael José Alves

Apyrase

Sinapis

10.1016/j.ijbiomac.2020.07.081

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Citations (7)

Semi-synthetic nanobody-ligand conjugates exhibit tunable signaling properties and enhanced transcriptional outputs at neurokinin receptor-1

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Nayara Braga Emídio Ross W. Cheloha

Antibodies have proven highly valuable for therapeutic development; however, they are typically poor candidates for applications that require activation of G protein-coupled receptors (GPCRs), the largest collection of targets for clinically approved drugs. Nanobodies (Nbs), the smallest antibody fragments retaining full antigen-binding capacity, have emerged as promising tools for pharmacologic applications, including GPCR modulation. Past work has shown that conjugation of Nbs with ligands can provide GPCR agonists that exhibit improved activity and selectivity compared to their parent ligands. The neurokinin-1 receptor (NK1R), a GPCR targeted for the treatment of pain, is activated by peptide agonists such as Substance P (SP) and neurokinin A (NKA), which induce signaling through multiple pathways (G

Conjugate

Tachykinin receptor 1

10.1101/2023.10.08.561411

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Citations (1)