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8FQ7

Nanobody with WIW inserted in CDR3 loop to Inhibit Growth of Alzheimer's Tau fibrils

Summary for 8FQ7
Entry DOI10.2210/pdb8fq7/pdb
DescriptorNanobody with WIW insert in CDR3 loop to target tau fibrils, GLYCEROL (3 entities in total)
Functional Keywordsanti-tau antibody, nanobody, immune system
Biological sourceCamelus dromedarius
Total number of polymer chains1
Total formula weight13860.28
Authors
Abskharon, R.,Sawaya, M.R.,Cascio, D.C.,Eisenberg, D.S. (deposition date: 2023-01-05, release date: 2023-10-04, Last modification date: 2024-10-30)
Primary citationAbskharon, R.,Pan, H.,Sawaya, M.R.,Seidler, P.M.,Olivares, E.J.,Chen, Y.,Murray, K.A.,Zhang, J.,Lantz, C.,Bentzel, M.,Boyer, D.R.,Cascio, D.,Nguyen, B.A.,Hou, K.,Cheng, X.,Pardon, E.,Williams, C.K.,Nana, A.L.,Vinters, H.V.,Spina, S.,Grinberg, L.T.,Seeley, W.W.,Steyaert, J.,Glabe, C.G.,Ogorzalek Loo, R.R.,Loo, J.A.,Eisenberg, D.S.
Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.
Proc.Natl.Acad.Sci.USA, 120:e2300258120-e2300258120, 2023
Cited by
PubMed Abstract: Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.
PubMed: 37801475
DOI: 10.1073/pnas.2300258120
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.4 Å)
Structure validation

239492

건을2025-07-30부터공개중

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