Multiple interests in structural models of DARC transmembrane protein

Smolarek, Dorota; Bertrand, Olivier; Czerwiński, Marcin; Colin, Yves; Etchebest, Catherine; Brevern, Alexandre G. de

doi:10.1016/j.tracli.2010.05.003

Cited by 13 publications

(15 citation statements)

References 148 publications

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“…Comparative molecular modelling had shown the difficulty to propose pertinent structural model of VHHs [26,[35][36], even with very sophisticated approaches as RosettaAntibody [71]. In fact, the results can be appreciated as less efficient than for classical antibodies as tested in AMA I and AMA II [88][89][90][91].…”

Section: Discussionmentioning

confidence: 99%

Global analysis of VHHs framework regions with a structural alphabet

Noël

Malpertuy²,

Brevern

2016

Biochimie

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The VHHs are antigen-binding region/domain of camelid heavy chain antibodies (HCAb). They have many interesting biotechnological and biomedical properties due to their small size, high solubility and stability, and high affinity and specificity for their antigens. HCAb and classical IgGs are evolutionary related and share a common fold. VHHs are composed of regions considered as constant, called the frameworks (FRs) connected by Complementarity Determining Regions (CDRs), a highly variable region that provide interaction with the epitope. Actually, no systematic structural analyses had been performed on VHH structures despite a significant number of structures. This work is the first study to analyse the structural diversity of FRs of VHHs. Using a structural alphabet that allows approximating the local conformation, we show that each of the four FRs do not have a unique structure but exhibit many structural variant patterns. Moreover, no direct simple link between the local conformational change and amino acid composition can be detected. These results indicate that long-range interactions affect the local conformation of FRs and impact the building of structural models.

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Section: Discussionmentioning

confidence: 99%

Global analysis of VHHs framework regions with a structural alphabet

Noël

Malpertuy²,

Brevern

2016

Biochimie

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“…A VHH antibody fragment against the atypical chemokine receptor Duffy antigen receptor for chemokines (DARC) has also been reported. Unlike the CXCR4 nanobody, the DARC VHH fragment has been generated solely against the N‐terminal domain of the receptor (Smolarek et al ., 2010). The CA52 nanobody binds to DARC with a very high affinity of 0.2 nM.…”

Section: Biological Therapeutics Targeting Chemokine Receptorsmentioning

confidence: 99%

“…It displaces the endogenous DARC ligand CXCL8 and was able to prevent the infection of red blood cells by Plasmodium vivax. As such, this nanobody may serve as a basis for the development of therapeutics against malaria (Handel and Horuk, 2010; Smolarek et al ., 2010).…”

Section: Biological Therapeutics Targeting Chemokine Receptorsmentioning

confidence: 99%

Pharmacological modulation of chemokine receptor function

Scholten¹,

Canals

Maussang³

et al. 2012

British J Pharmacology

229

254

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G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered.

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“…Beyond being receptors for P. vivax and various chemokines [19], DARC proteins have clinical and biological significance and have been reported to be associated with transfusion incompatibility and hemolytic disease of the newborn [20]–[22]. It is also implicated in several inflammatory diseases, and cancer, and might play a role in HIV infection and AIDS [23]–[26]. Recently, a previously unreported function of this receptor has been described in P. falciparum infection, in which DARC proteins seem to be essential for platelet-mediated killing of P. falciparum parasites [27].…”

Section: Introductionmentioning

confidence: 99%

Duffy Antigen Receptor for Chemokine (DARC) Polymorphisms and Its Involvement in Acquisition of Inhibitory Anti-Duffy Binding Protein II (DBPII) Immunity

et al. 2014

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The Plasmodium vivax Duffy binding protein (PvDBP) and its erythrocytic receptor, the Duffy antigen receptor for chemokines (DARC), are involved in the major P. vivax erythrocyte invasion pathway. An open cohort study to analyze DARC genotypes and their relationship to PvDBP immune responses was carried out in 620 volunteers in an agricultural settlement of the Brazilian Amazon. Three cross-sectional surveys were conducted at 6-month intervals, comprising 395, 410, and 407 subjects, respectively. The incidence rates of P. vivax infection was 2.32 malaria episodes per 100 person-months under survey (95% confidence interval [CI] of 1.92-2.80/100 person-month) and, of P. falciparum, 0.04 per 100 person-months (95% CI of 0.007–0.14/100 person-month). The distribution of DARC genotypes was consistent with the heterogeneous ethnic origins of the Amazon population, with a predominance of non-silent DARC alleles: FY*A > FY*B. The 12-month follow-up study demonstrated no association between DARC genotypes and total IgG antibodies as measured by ELISA targeting PvDBP (region II, DBPII or regions II–IV, DBPII-IV). The naturally acquired DBPII specific binding inhibitory antibodies (BIAbs) tended to be more frequent in heterozygous individuals carrying a DARC-silent allele (FY*BES). These results provide evidence that DARC polymorphisms may influence the naturally acquired inhibitory anti-Duffy binding protein II immunity.

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Multiple interests in structural models of DARC transmembrane protein

Cited by 13 publications

References 148 publications

Global analysis of VHHs framework regions with a structural alphabet

Global analysis of VHHs framework regions with a structural alphabet

Pharmacological modulation of chemokine receptor function

Duffy Antigen Receptor for Chemokine (DARC) Polymorphisms and Its Involvement in Acquisition of Inhibitory Anti-Duffy Binding Protein II (DBPII) Immunity

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