 |
PDBsum entry 3s8z
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Signaling protein
|
PDB id
|
|
|
|
3s8z
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structures of the extracellular domain of lrp6 and its complex with dkk1.
|
|
|
Authors
|
|
Z.Cheng,
T.Biechele,
Z.Wei,
S.Morrone,
R.T.Moon,
L.Wang,
W.Xu.
|
|
|
Ref.
|
|
Nat Struct Biol, 2011,
18,
1204-1210.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
