Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold
Abstract
The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting.
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Atomic-level control of antigenicity increasingly appears to be within the reach of structure-based design.
“Importantly, atomic-level control of antigenicity increasingly appears to be within the reach of structure-based design (16, 39, 40).”
From Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus (2013) · cites this paper as [40]
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Self-citationComputational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin
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- Authors
- Azoitei, M. L., Correia, B. E., Ban, Y.-E. A., Carrico, C., Kalyuzhniy, O., Chen, L., Schroeter, A., Huang, P.-S., McLellan, J. S., Kwong, P. D., Baker, D., Strong, R. K., & Schief, W. R.
- Affiliations
- University of Washington (US)
- National Institute of Allergy and Infectious Diseases (US)
- Howard Hughes Medical Institute (US)
- Fred Hutch Cancer Center (US)
- Scripps Research Institute (US)
- Corresponding author
- Azoitei, Mihai L.
- Correia, Bruno E.
- Schief, William R.
- ORCID
- Venue
- Science
- Published
- 2011-10-21
- Volume
- 334
- Issue
- 6054
- Pages
- 373-376
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2166740197
- Cited by
- 224
- References
- 2
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 15 · 2021: 15 · 2020: 10 · 2019: 11 · 2018: 11 · 2017: 15 · 2016: 10 · 2015: 20 · 2014: 23 · 2013: 37 · 2012: 29
- FWCI
- 11.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- antibody-antigen binding, computational protein design, side-chain grafting, conformational epitopes, cross-neutralizing antibodies
- MeSH terms
- Algorithms, Amino Acid Sequence, Antibodies, Monoclonal, Antibody Affinity, Antibody Specificity, Epitopes, Computer Simulation, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Engineering, HIV Antibodies, HIV Envelope Protein gp120, CD4 Antigens, Mutagenesis, Crystallography, X-Ray, Molecular Mimicry, Computational Biology, Surface Plasmon Resonance, Amino Acid Motifs, Protein Interaction Domains and Motifs, Antibodies, Neutralizing
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