3S94

Crystal structure of LRP6-E1E2

Summary for 3S94

• Entry DOI: 10.2210/pdb3s94/pdb
• Related: 3S8V 3S8Z
• Descriptor: Low-density lipoprotein receptor-related protein 6, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: wnt, receptor, lrp5, lrp6, ldl receptor-like protein, dickkopf (dkk), ywtd b-propeller, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 141350.15

Authors

Cheng, Z.,Xu, W. (deposition date: 2011-05-31, release date: 2011-11-02, Last modification date: 2024-10-16)

Primary citation

Cheng, Z.,Biechele, T.,Wei, Z.,Morrone, S.,Moon, R.T.,Wang, L.,Xu, W.
Crystal structures of the extracellular domain of LRP6 and its complex with DKK1.
Nat.Struct.Mol.Biol., 18:1204-1210, 2011

PubMed Abstract: Low-density-lipoprotein (LDL) receptor-related proteins 5 and 6 (LRP5/6) are Wnt co-receptors essential for Wnt/β-catenin signaling. Dickkopf 1 (DKK1) inhibits Wnt signaling by interacting with the extracellular domains of LRP5/6 and is a drug target for multiple diseases. Here we present the crystal structures of a human LRP6-E3E4-DKK1 complex and the first and second halves of human LRP6's four propeller-epidermal growth factor (EGF) pairs (LRP6-E1E2 and LRP6-E3E4). Combined with EM analysis, these data demonstrate that LRP6-E1E2 and LRP6-E3E4 form two rigid structural blocks, with a short intervening hinge that restrains their relative orientation. The C-terminal domain of DKK1 (DKK1c) interacts with the top surface of the LRP6-E3 YWTD propeller and given their structural similarity, probably also that of the LRP6-E1 propeller, through conserved hydrophobic patches buttressed by a network of salt bridges and hydrogen bonds. Our work provides key insights for understanding LRP5/6 structure and the interaction of LRP5/6 with DKK, as well as for drug discovery.

PubMed: 21984209
DOI: 10.1038/nsmb.2139

Experimental method

X-RAY DIFFRACTION (2.8 Å)