The third-dimensional structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: A combined two-dimensional NMR, homology, and molecular modeling approach

Kleinjung, Jens; Petit, Marie-Christine; Orlewski, Piotr; Mamalaki, Avgi; Tzartos, Socrates J.; Tsikaris, Vassilios; Sakarellos‐Daitsiotis, Maria; Sakarellos, Constantinos; Marraud, Michel; Cung, Manh Thông

doi:10.1002/(sici)1097-0282(200002)53:2<113::aid-bip1>3.0.co;2-j

Cited by 15 publications

(18 citation statements)

References 51 publications

(52 reference statements)

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“…Interestingly, superposition of the structure of Fab198 onto that of Fab35 in the ternary complex shows that these two Fabs share not only a conserved immunoglobulin fold but also a similar antigen-binding site (Figure 4a). As such, the MIR loop fits well into the pocket surrounded by the CDR-H2, CDR-H3 and CDR-L3 loops of Fab198, as predicated by previous modeling studies (Kleinjung et al, 2000). The CDR-H2 loop of Fab198 is also in position to interact with the N-terminal helix adjacent to the MIR (Figure 4b).…”

Section: Resultssupporting

confidence: 79%

“…Since then, extensive efforts have been put into characterizing the interactions between MG antibodies and nAChR using biochemical (Barkas et al, 1988; Tzartos et al, 1988; Das and Lindstrom, 1989; Saedi et al, 1990; Papadouli et al, 1990, 1993; Luo et al, 2009; Morell et al, 2014), structural (Dellisanti et al, 2007a; Beroukhim and Unwin, 1995; Kontou et al, 2000; Poulas et al, 2001), and modeling approaches (Kleinjung et al, 2000). These studies aimed to understand the basic mechanisms of MG and also the structure/function of nAChR in order to develop effective diagnosis and treatment for MG.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

Noridomi

Watanabe

Hansen

et al. 2017

eLife

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The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.DOI: http://dx.doi.org/10.7554/eLife.23043.001

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Section: Resultssupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

Noridomi

Watanabe

Hansen

et al. 2017

eLife

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“…A common reason for missing electron density is that the unobserved atom, side chain, residue or region fails to scatter X‐rays coherently, because of variation in position from one protein to the next; for example, the unobserved atoms can be flexible or disordered. Two proteins are exceptions to this: (a) an antibody molecule in which the Gly‐rich TR represents a crosslink between two domains (PDB code: 1F3R) [25]; and (b) a substrate with an (Arg‐Ser) 8 tract that was cocrystallized with protein kinase (PDB code: 3BEG) [26]. This Arg‐rich peptide, being alone in solution, will most probably be unstructured, owing to the absence of nonpolar residues and the presence of eight Arg residues carrying a charge of the same sign.…”

Section: Resultsmentioning

confidence: 99%

“…The following tags were assigned to each analysed region with TRs: Sn and Sd, fragments containing secondary structures from natural and designed proteins, respectively; Ln and Ld, fragments connecting secondary structures from natural and designed proteins, respectively; Un and Ud, fragments whose structure was not determined from natural and designed proteins, respectively. Gly-rich TR represents a crosslink between two domains (PDB code: 1F3R) [25]; and (b) a substrate with an (Arg-Ser) 8 tract that was cocrystallized with protein kinase (PDB code: 3BEG) [26]. This Arg-rich peptide, being alone in solution, will most probably be unstructured, owing to the absence of nonpolar residues and the presence of eight Arg residues carrying a charge of the same sign.…”

Section: Resultsmentioning

confidence: 99%

Protein tandem repeats – the more perfect, the less structured

et al. 2010

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We analysed the structural properties of protein regions containing arrays of perfect and nearly perfect tandem repeats. Naturally occurring proteins with perfect repeats are practically absent among the proteins with known 3D structures. The great majority of such regions in the Protein Data Bank are found in the proteins designed de novo. The abundance of natural structured proteins with tandem repeats is inversely correlated with the repeat perfection: the chance of finding natural structured proteins in the Protein Data Bank increases with a decrease in the level of repeat perfection. Prediction of intrinsic disorder within the tandem repeats in the SwissProt proteins supports the conclusion that the level of repeat perfection correlates with their tendency to be unstructured. This correlation is valid across the various species and subcellular localizations, although the level of disordered tandem repeats varies significantly between these datasets. On average, in prokaryotes, tandem repeats of cytoplasmic proteins were predicted to be the most structured, whereas in eukaryotes, the most structured portion of the repeats was found in the membrane proteins. Our study supports the hypothesis that, in general, the repeat perfection is a sign of recent evolutionary events rather than of exceptional structural and (or) functional importance of the repeat residues.

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“…Such a superposition yields an rms deviation of 1.0 Å. A model of the complex formed between the antibody and the MIR peptide was published 35. Combination of that model and the superposition described above yields a very interesting impression of the antibody binding to AChBP, in which no major clashes occur (Fig.…”

Section: The Mir Regionmentioning

confidence: 96%

Structure and Function of AChBP, Homologue of the Ligand‐Binding Domain of the Nicotinic Acetylcholine Receptor

Smit

Brejc

Syed

et al. 2003

Annals of the New York Academy of Sciences

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Acetylcholine-binding protein (AChBP) is a novel protein with high similarity to the extracellular domain of the nicotinic acetylcholine receptor. AChBP lacks the transmembrane domains and intracellular loops typical for the nAChRs. AChBP is secreted from glia cells in the central nervous system of the freshwater snail, Lymnaea stagnalis, where it modulates synaptic transmission. AChBP forms homopentamers with pharmacology that resembles the alpha(7)-type of nicotinic receptors. As such, AChBP is a good model for the ligand-binding domain of the nAChRs. In the crystal structure of AChBP at 2.7 A, each protomer has a modified immunoglobulin fold. Almost all residues previously shown to be involved in ligand binding in the nicotinic receptor are found in a pocket at the subunit interface, which is lined with aromatic residues. The AChBP crystal structure explains many of the biochemical studies on the nicotinic acetylcholine receptors. Surprisingly, the interface between protomers is relatively weakly conserved between families in the superfamily of pentameric ligand-gated ion channels. The lack of conservation has implications for the mechanism of gating of the ion channels.

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The third-dimensional structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: A combined two-dimensional NMR, homology, and molecular modeling approach

Cited by 15 publications

References 51 publications

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

Protein tandem repeats – the more perfect, the less structured

Structure and Function of AChBP, Homologue of the Ligand‐Binding Domain of the Nicotinic Acetylcholine Receptor

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