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Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications.

Blech M, Seeliger D, Kistler B, Bauer MM, Hafner M, Hörer S, Zeeb M, Nar H, Park JE
Biochem J 447 205-15 (2012)
Cited: 13 times
EuropePMC logo PMID: 22839360

Abstract

Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen-autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF-GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.

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  1. Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis. Radamaker L, Baur J, Huhn S, Haupt C, Hegenbart U, Schönland S, Bansal A, Schmidt M, Fändrich M. Nat Commun 12 875 (2021)
  2. The structures of secretory and dimeric immunoglobulin A. Kumar Bharathkar S, Parker BW, Malyutin AG, Haloi N, Huey-Tubman KE, Tajkhorshid E, Stadtmueller BM. Elife 9 e56098 (2020)
  3. Poorly Expressed Alleles of Several Human Immunoglobulin Heavy Chain Variable Genes are Common in the Human Population. Ohlin M. Front Immunol 11 603980 (2020)
  4. Crystal structure of the Fab region of a neutralizing antibody against granulocyte-macrophage colony-stimulating factor. Angkawidjaja C, Torashima T. Acta Crystallogr F Struct Biol Commun 75 634-639 (2019)


Articles citing this publication (9)

  1. Modeling and docking of antibody structures with Rosetta. Weitzner BD, Jeliazkov JR, Lyskov S, Marze N, Kuroda D, Frick R, Adolf-Bryfogle J, Biswas N, Dunbrack RL, Gray JJ. Nat Protoc 12 401-416 (2017)
  2. Prediction and Reduction of the Aggregation of Monoclonal Antibodies. van der Kant R, Karow-Zwick AR, Van Durme J, Blech M, Gallardo R, Seeliger D, Aßfalg K, Baatsen P, Compernolle G, Gils A, Studts JM, Schulz P, Garidel P, Schymkowitz J, Rousseau F. J Mol Biol 429 1244-1261 (2017)
  3. Epitope mapping by solution NMR spectroscopy. Bardelli M, Livoti E, Simonelli L, Pedotti M, Moraes A, Valente AP, Varani L. J Mol Recognit 28 393-400 (2015)
  4. Structural Analysis of Der p 1-Antibody Complexes and Comparison with Complexes of Proteins or Peptides with Monoclonal Antibodies. Osinski T, Pomés A, Majorek KA, Glesner J, Offermann LR, Vailes LD, Chapman MD, Minor W, Chruszcz M. J Immunol 195 307-316 (2015)
  5. Molecular basis of in vitro affinity maturation and functional evolution of a neutralizing anti-human GM-CSF antibody. Eylenstein R, Weinfurtner D, Härtle S, Strohner R, Böttcher J, Augustin M, Ostendorp R, Steidl S. MAbs 8 176-186 (2016)
  6. Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis. Salvator H, Cheng A, Rosen LB, Williamson PR, Bennett JE, Kashyap A, Ding L, Kwon-Chung KJ, Namkoong H, Zerbe CS, Holland SM. Respir Res 23 280 (2022)
  7. The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeutic opportunities. Dhagat U, Hercus TR, Broughton SE, Nero TL, Cheung Tung Shing KS, Barry EF, Thomson CA, Bryson S, Pai EF, McClure BJ, Schrader JW, Lopez AF, Parker MW. MAbs 10 1018-1029 (2018)
  8. Familial Association of Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Inflammatory Bowel Disease. Wright SS, Trauernicht A, Bonkowski E, McCall CA, Maier EA, Bezold R, Lake K, Chalk C, Trapnell BC, Kim MO, Kugathasan S, Denson LA. J Pediatr Gastroenterol Nutr 66 767-772 (2018)
  9. NMR Based SARS-CoV-2 Antibody Screening. Schoenle MV, Li Y, Yuan M, Clarkson MW, Wilson IA, Peti W, Page R. J Am Chem Soc 143 7930-7934 (2021)


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