3SOB

The structure of the first YWTD beta propeller domain of LRP6 in complex with a FAB

Summary for 3SOB

• Entry DOI: 10.2210/pdb3sob/pdb
• Descriptor: antibody light chain, Low-density lipoprotein receptor-related protein 6, antibody heavy chain, ... (5 entities in total)
• Functional Keywords: beta propeller, protein binding-immune system complex, protein binding/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: O75581
• Total number of polymer chains: 3
• Total formula weight: 88522.46

Authors

Wang, W.,Bourhis, E.,Tam, C.,Zhang, Y.,Rouge, L.,Wu, Y.,Franke, Y.,Cochran, A.G. (deposition date: 2011-06-30, release date: 2011-09-21, Last modification date: 2024-10-30)

Primary citation

Bourhis, E.,Wang, W.,Tam, C.,Hwang, J.,Zhang, Y.,Spittler, D.,Huang, O.W.,Gong, Y.,Estevez, A.,Zilberleyb, I.,Rouge, L.,Chiu, C.,Wu, Y.,Costa, M.,Hannoush, R.N.,Franke, Y.,Cochran, A.G.
Wnt antagonists bind through a short peptide to the first beta-propeller domain of LRP5/6.
Structure, 19:1433-1442, 2011

PubMed Abstract: The Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic targets in diseases involving bone loss or damage. It has been appreciated that Wnt coreceptors LRP5/6 are also important, as human missense mutations that result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to the E1 propeller domain of LRP5. Here, we report a crystal structure of LRP6 E1 bound to an antibody, revealing that the E1 domain is a peptide recognition module. Remarkably, the consensus E1 binding sequence is a close match to a conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We show that this motif is important for DKK1 and SOST binding to LRP6 and for inhibitory function, providing a detailed structural explanation for the effect of the BMD mutations.

PubMed: 21944579
DOI: 10.1016/j.str.2011.07.005

Experimental method

X-RAY DIFFRACTION (1.9 Å)