PDBsum entry 3s94

Signaling protein

PDB id: 3s94

Contents

Protein chain

587 a.a.

Ligands

NAG-NAG ×2

NAG

PDB id:

3s94

Name:

Signaling protein

Title:

Crystal structure of lrp6-e1e2

Structure:

Low-density lipoprotein receptor-related protein 6. Chain: a, b. Fragment: e1e2, residues 20-630. Synonym: lrp-6. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lrp6. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.80Å R-factor: 0.240 R-free: 0.296

Authors:

Z.Cheng,W.Xu

Key ref:

Z.Cheng et al. (2011). Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat Struct Biol, 18, 1204-1210. PubMed id: 21984209

Date:

31-May-11 Release date: 02-Nov-11

Protein chains

O75581  (LRP6_HUMAN) -  Low-density lipoprotein receptor-related protein 6 from Homo sapiens

Seq: 1613 a.a.

Struc: 587 a.a.

Nat Struct Biol 18:1204-1210 (2011)

PubMed id: 21984209

Crystal structures of the extracellular domain of LRP6 and its complex with DKK1.

Z.Cheng, T.Biechele, Z.Wei, S.Morrone, R.T.Moon, L.Wang, W.Xu.

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.