8u4v

From Proteopedia

Cryo-EM structure of human claudin-4 complex with Clostridium perfringens enterotoxin C-terminal domain, sFab COP-1, and Nanobody

Structural highlights

8u4v is a 5 chain structure with sequence from Clostridium perfringens, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.99Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CLD4_HUMAN CLDN4 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.

Function

CLD4_HUMAN Channel-forming tight junction protein that mediates paracellular chloride transport in the kidney. Plays a critical role in the paracellular reabsorption of filtered chloride in the kidney collecting ducts. Claudins play a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.[UniProtKB:O35054]

Publication Abstract from PubMed

Claudins are a 27-member family of ~25 kDa membrane proteins that integrate into tight junctions to form molecular barriers at the paracellular spaces between endothelial and epithelial cells. As the backbone of tight junction structure and function, claudins are attractive targets for modulating tissue permeability to deliver drugs or treat disease. However, structures of claudins are limited due to their small sizes and physicochemical properties-these traits also make therapy development a challenge. Here we report the development of a synthetic antibody fragment (sFab) that binds human claudin-4 and the determination of a high-resolution structure of it bound to claudin-4/enterotoxin complexes using cryogenic electron microscopy. Structural and biophysical results reveal this sFabs mechanism of select binding to human claudin-4 over other homologous claudins and establish the ability of sFabs to bind hard-to-target claudins to probe tight junction structure and function. The findings provide a framework for tight junction modulation by sFabs for tissue-selective therapies.

Structural and biophysical insights into targeting of claudin-4 by a synthetic antibody fragment.,Erramilli SK, Dominik PK, Ogbu CP, Kossiakoff AA, Vecchio AJ Commun Biol. 2024 Jun 17;7(1):733. doi: 10.1038/s42003-024-06437-6. PMID:38886509^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Erramilli SK, Dominik PK, Ogbu CP, Kossiakoff AA, Vecchio AJ. Structural and biophysical insights into targeting of claudin-4 by a synthetic antibody fragment. Commun Biol. 2024 Jun 17;7(1):733. PMID:38886509 doi:10.1038/s42003-024-06437-6