Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.

ABSTRACT:

Background

Hemophilia A arises from dysfunctional or deficient coagulation factor (F)VIII and leads to inefficient fibrin clot formation and uncontrolled bleeding events. The development of antibody inhibitors is a clinical complication in hemophilia A patients receiving FVIII replacement therapy. LE2E9 is an anti-C1 domain inhibitor previously isolated from a mild/moderate hemophilia A patient and disrupts FVIII interactions with von Willebrand factor and FIXa, though the intermolecular contacts that underpin LE2E9-mediated FVIII neutralization are undefined.

Objectives

To determine the structure of the complex between FVIII and LE2E9 and characterize its mechanism of inhibition.

Methods

FVIII was bound to the antigen binding fragment (Fab) of NB2E9, a recombinant co

SUBMITTER: Childers KC 

PROVIDER: S-EPMC11343672 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature