4CNM: Crystal Structure Of Human 5t4 (wnt-activated Inhibitory Factor 1, Trophoblast Glycoprotein)

The tumor antigen 5T4/WAIF1 (Wnt-activated inhibitory factor 1; also known as Trophoblast glycoprotein TPBG) is a cell surface protein targeted in multiple cancer immunotherapy clinical trials. Recently, it has been shown that 5T4/WAIF1 inhibits Wnt/beta-catenin signaling, a signaling system central to many developmental and pathological processes. Wnt/beta-catenin signaling is controlled by multiple inhibitors and activators. Here, we report crystal structures for the extracellular domain of 5T4/WAIF1 at 1.8 A resolution. They reveal a highly glycosylated, rigid core, comprising eight leucine-rich repeats (LRRs), which serves as a platform to present evolutionarily conserved surface residues in the N-terminal LRR1. Structural and cell-based analyses, coupled with previously reported in vivo data, suggest that Tyr325 plus the LRR1 surface centered on a second exposed aromatic residue, Phe97, are essential for inhibition of Wnt/beta-catenin signaling. These results provide a structural basis for the development of 5T4/WAIF1-targeted therapies that preserve or block 5T4/WAIF1-mediated inhibition of Wnt/beta-catenin signaling.
PDB ID: 4CNMDownload
MMDB ID: 117791
PDB Deposition Date: 2014/1/23
Updated in MMDB: 2014/05
Experimental Method:
x-ray diffraction
Resolution: 1.75  Å
Source Organism:
Similar Structures:
Biological Unit for 4CNM: monomeric; determined by author and by software (PISA)
Molecular Components in 4CNM
Label Count Molecule
Protein (1 molecule)
Trophoblast Glycoprotein(Gene symbol: TPBG)
Molecule annotation
Chemicals (12 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB