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Title | Engineering the ADDobody protein scaffold for generation of high-avidity ADDomer super-binders. |
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Journal, issue, pages | Structure, Vol. 32, Issue 3, Page 342-351.e6, Year 2024 |
Publish date | Mar 7, 2024 |
Authors | Dora Buzas / Huan Sun / Christine Toelzer / Sathish K N Yadav / Ufuk Borucu / Gunjan Gautam / Kapil Gupta / Joshua C Bufton / Julien Capin / Richard B Sessions / Frederic Garzoni / Imre Berger / Christiane Schaffitzel / |
PubMed Abstract | Adenovirus-derived nanoparticles (ADDomer) comprise 60 copies of adenovirus penton base protein (PBP). ADDomer is thermostable, rendering the storage, transport, and deployment of ADDomer-based ...Adenovirus-derived nanoparticles (ADDomer) comprise 60 copies of adenovirus penton base protein (PBP). ADDomer is thermostable, rendering the storage, transport, and deployment of ADDomer-based therapeutics independent of a cold chain. To expand the scope of ADDomers for new applications, we engineered ADDobodies, representing PBP crown domain, genetically separated from PBP multimerization domain. We inserted heterologous sequences into hyper-variable loops, resulting in monomeric, thermostable ADDobodies expressed at high yields in Escherichia coli. The X-ray structure of an ADDobody prototype validated our design. ADDobodies can be used in ribosome display experiments to select a specific binder against a target, with an enrichment factor of ∼10-fold per round. ADDobodies can be re-converted into ADDomers by genetically reconnecting the selected ADDobody with the PBP multimerization domain from a different species, giving rise to a multivalent nanoparticle, called Chimera, confirmed by a 2.2 Å electron cryo-microscopy structure. Chimera comprises 60 binding sites, resulting in ultra-high, picomolar avidity to the target. |
External links | Structure / PubMed:38198950 |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.2 - 3.17 Å |
Structure data | EMDB-18323, PDB-8qbx: PDB-8coi: PDB-8qb3: |
Chemicals | ChemComp-ZN: |
Source |
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Keywords | VIRAL PROTEIN / penton base / crown domain / human adenovirus / Adenovirus capsid / Penton base protein / Structural viral protein / VIRUS LIKE PARTICLE / Adenovirus / capsid protein / virus-like particle |