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Robust Antibody-Antigen Complexes Prediction Generated by Combining Sequence Analyses, Mutagenesis, In Vitro Evolution, X-ray Crystallography and In Silico Docking.

Loyau J, Didelot G, Malinge P, Ravn U, Magistrelli G, Depoisier JF, Pontini G, Poitevin Y, Kosco-Vilbois M, Fischer N, Thore S, Rousseau F
J Mol Biol 427 2647-62 (2015)
Cited: 7 times
EuropePMC logo PMID: 26013163

Abstract

Hu 15C1 is a potent anti-human Toll-like receptor 4 (TLR4) neutralizing antibody. To better understand the molecular basis of its biological activity, we used a multidisciplinary approach to generate an accurate model of the Hu 15C1-TLR4 complex. By combining site-directed mutagenesis, in vitro antibody evolution, affinity measurements and X-ray crystallography of Fab fragments, we identified key interactions across the Hu 15C1-TLR4 interface. These contact points were used as restraints to predict the structure of the Fab region of Hu 15C1 bound to TLR4 using computational molecular docking. This model was further evaluated and validated by additional site-directed mutagenesis studies. The predicted structure of the Hu 15C1-TLR4 complex indicates that the antibody antagonizes the receptor dimerization necessary for its activation. This study exemplifies how iterative cycles of antibody engineering can facilitate the discovery of components of antibody-target interactions.

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Reviews citing this publication (1)

  1. Monoclonal Antibody to CD14, TLR4, or CD11b: Impact of Epitope and Isotype Specificity on ROS Generation by Human Granulocytes and Monocytes. Kabanov DS, Grachev SV, Prokhorenko IR. Oxid Med Cell Longev 2020 5708692 (2020)

Articles citing this publication (5)

  1. Structural prediction of antibody-APRIL complexes by computational docking constrained by antigen saturation mutagenesis library data. Wollacott AM, Robinson LN, Ramakrishnan B, Tissire H, Viswanathan K, Shriver Z, Babcock GJ. J Mol Recognit 32 e2778 (2019)
  2. Letter An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody. Tsukamoto H, Yamagata Y, Ukai I, Takeuchi S, Okubo M, Kobayashi Y, Kozakai S, Kubota K, Numasaki M, Kanemitsu Y, Matsumoto Y, Tomioka Y. FEBS Lett. 591 2406-2416 (2017)
  3. Functional antibody characterization via direct structural analysis and information-driven protein-protein docking. Depetris RS, Lu D, Polonskaya Z, Zhang Z, Luna X, Tankard A, Kolahi P, Drummond M, Williams C, Ebert MCCJC, Patel JP, Poyurovsky MV. Proteins 90 919-935 (2022)
  4. Development a novel multiepitope DNA vaccine against human SARS coronavirus-2: an immunoinformatic designing study. Nemati AS, Mirzaie S, Masoumian MR, Sheikhi F, Jamalan M. Turk J Biol 46 263-276 (2022)
  5. Native peptide mapping - A simple method to routinely monitor higher order structure changes and relation to functional activity. Degueldre M, Wielant A, Girot E, Burkitt W, O'Hara J, Debauve G, Gervais A, Jone C. MAbs 11 1391-1401 (2019)


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