6H15

Structure of LRP6 P3E3P4E4 in complex with VHH L-P2-B10

Summary for 6H15

• Entry DOI: 10.2210/pdb6h15/pdb
• Descriptor: Low-density lipoprotein receptor-related protein 6, VHH L-P2-B10, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: inhibitor, complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 171064.11

Authors

Gros, P.,van Scherpenzeel, R.C. (deposition date: 2018-07-11, release date: 2019-01-30, Last modification date: 2024-11-06)

Primary citation

Fenderico, N.,van Scherpenzeel, R.C.,Goldflam, M.,Proverbio, D.,Jordens, I.,Kralj, T.,Stryeck, S.,Bass, T.Z.,Hermans, G.,Ullman, C.,Aastrup, T.,Gros, P.,Maurice, M.M.
Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells.
Nat Commun, 10:365-365, 2019

PubMed Abstract: Wnt-induced β-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment of such cancer subsets. Here, we employ CIS display technology to identify single-domain antibody fragments (VHH) that bind the LRP6 P3E3P4E4 region with nanomolar affinity and strongly inhibit Wnt3/3a-induced β-catenin-mediated transcription in cells, while leaving Wnt1 responses unaffected. Structural analysis reveal that individual VHHs variably employ divergent antigen-binding regions to bind a similar surface in the third β-propeller of LRP5/6, sterically interfering with Wnt3/3a binding. Importantly, anti-LRP5/6 VHHs block the growth of Wnt-hypersensitive Rnf43/Znrf3-mutant intestinal organoids through stem cell exhaustion and collective terminal differentiation. Thus, VHH-mediated targeting of LRP5/6 provides a promising differentiation-inducing strategy for treatment of Wnt-hypersensitive tumors.

PubMed: 30664649
DOI: 10.1038/s41467-018-08172-z

Experimental method

X-RAY DIFFRACTION (2.6 Å)