9B9J

Integrin alpha-5 beta-1 in complex with BIIG2 Fab

Summary for 9B9J

• Entry DOI: 10.2210/pdb9b9j/pdb
• Related: 8R38
• EMDB information: 44386
• Descriptor: Integrin alpha-5 light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, Integrin beta-1, ... (10 entities in total)
• Functional Keywords: integrin, antibody fab, inhibitory, signaling protein, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 242698.00

Authors

Nguyen, A.,Azumaya, C.M.,Campbell, M.G. (deposition date: 2024-04-02, release date: 2025-02-05, Last modification date: 2025-10-22)

Primary citation

Nguyen, A.,Heim, J.B.,Cordara, G.,Chan, M.C.,Johannesen, H.,Charlesworth, C.,Li, M.,Azumaya, C.M.,Madden, B.,Krengel, U.,Meves, A.,Campbell, M.G.
Shared ligand-blocking mechanism but distinct conformational modulation by alpha 5-targeting antibodies BIIG2 and MINT1526A.
Biorxiv, 2025

PubMed Abstract: Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful due to poor efficacy and off-target effects. A contributing factor is our limited understanding of how integrin conformation influences interactions with therapeutics. Using cell-based functional assays, patient derived xenografts, biophysics, and electron microscopy, we shed light on these relationships by characterizing two anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity, reduce angiogenesis , and bind overlapping epitopes that block fibronectin binding. However, using cryoEM, we reveal that while BIIG2 binding doesn't alter the conformational states, MINT1526A restricts α5β1's range of flexibility. These insights can guide which aspects to prioritize and improve the design of future integrin-targeted therapeutics.

PubMed: 39829743
DOI: 10.1101/2025.01.08.631572

Experimental method

ELECTRON MICROSCOPY (2.6 Å)