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Structural diversity in a human antibody germline library
To support antibody therapeutic development, the crystal structures of a set of 16 germline variants composed of 4 different kappa light chains paired with 4 different heavy chains have been determined. All four heavy chains of the antigen-binding fragments (Fabs) have the same complementarity-deter...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968113/ https://www.ncbi.nlm.nih.gov/pubmed/27210805 http://dx.doi.org/10.1080/19420862.2016.1190060 |
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author | Teplyakov, Alexey Obmolova, Galina Malia, Thomas J. Luo, Jinquan Muzammil, Salman Sweet, Raymond Almagro, Juan Carlos Gilliland, Gary L. |
author_facet | Teplyakov, Alexey Obmolova, Galina Malia, Thomas J. Luo, Jinquan Muzammil, Salman Sweet, Raymond Almagro, Juan Carlos Gilliland, Gary L. |
author_sort | Teplyakov, Alexey |
collection | PubMed |
description | To support antibody therapeutic development, the crystal structures of a set of 16 germline variants composed of 4 different kappa light chains paired with 4 different heavy chains have been determined. All four heavy chains of the antigen-binding fragments (Fabs) have the same complementarity-determining region (CDR) H3 that was reported in an earlier Fab structure. The structure analyses include comparisons of the overall structures, canonical structures of the CDRs and the VH:VL packing interactions. The CDR conformations for the most part are tightly clustered, especially for the ones with shorter lengths. The longer CDRs with tandem glycines or serines have more conformational diversity than the others. CDR H3, despite having the same amino acid sequence, exhibits the largest conformational diversity. About half of the structures have CDR H3 conformations similar to that of the parent; the others diverge significantly. One conclusion is that the CDR H3 conformations are influenced by both their amino acid sequence and their structural environment determined by the heavy and light chain pairing. The stem regions of 14 of the variant pairs are in the ‘kinked’ conformation, and only 2 are in the extended conformation. The packing of the VH and VL domains is consistent with our knowledge of antibody structure, and the tilt angles between these domains cover a range of 11 degrees. Two of 16 structures showed particularly large variations in the tilt angles when compared with the other pairings. The structures and their analyses provide a rich foundation for future antibody modeling and engineering efforts. |
format | Online Article Text |
id | pubmed-4968113 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-49681132016-08-23 Structural diversity in a human antibody germline library Teplyakov, Alexey Obmolova, Galina Malia, Thomas J. Luo, Jinquan Muzammil, Salman Sweet, Raymond Almagro, Juan Carlos Gilliland, Gary L. MAbs Report To support antibody therapeutic development, the crystal structures of a set of 16 germline variants composed of 4 different kappa light chains paired with 4 different heavy chains have been determined. All four heavy chains of the antigen-binding fragments (Fabs) have the same complementarity-determining region (CDR) H3 that was reported in an earlier Fab structure. The structure analyses include comparisons of the overall structures, canonical structures of the CDRs and the VH:VL packing interactions. The CDR conformations for the most part are tightly clustered, especially for the ones with shorter lengths. The longer CDRs with tandem glycines or serines have more conformational diversity than the others. CDR H3, despite having the same amino acid sequence, exhibits the largest conformational diversity. About half of the structures have CDR H3 conformations similar to that of the parent; the others diverge significantly. One conclusion is that the CDR H3 conformations are influenced by both their amino acid sequence and their structural environment determined by the heavy and light chain pairing. The stem regions of 14 of the variant pairs are in the ‘kinked’ conformation, and only 2 are in the extended conformation. The packing of the VH and VL domains is consistent with our knowledge of antibody structure, and the tilt angles between these domains cover a range of 11 degrees. Two of 16 structures showed particularly large variations in the tilt angles when compared with the other pairings. The structures and their analyses provide a rich foundation for future antibody modeling and engineering efforts. Taylor & Francis 2016-05-21 /pmc/articles/PMC4968113/ /pubmed/27210805 http://dx.doi.org/10.1080/19420862.2016.1190060 Text en © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
spellingShingle | Report Teplyakov, Alexey Obmolova, Galina Malia, Thomas J. Luo, Jinquan Muzammil, Salman Sweet, Raymond Almagro, Juan Carlos Gilliland, Gary L. Structural diversity in a human antibody germline library |
title | Structural diversity in a human antibody germline library |
title_full | Structural diversity in a human antibody germline library |
title_fullStr | Structural diversity in a human antibody germline library |
title_full_unstemmed | Structural diversity in a human antibody germline library |
title_short | Structural diversity in a human antibody germline library |
title_sort | structural diversity in a human antibody germline library |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968113/ https://www.ncbi.nlm.nih.gov/pubmed/27210805 http://dx.doi.org/10.1080/19420862.2016.1190060 |
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