How Natalizumab Binds and Antagonizes α4 Integrins

Abstract

Background: How does the multiple sclerosis therapeutic antibody natalizumab bind to ␣4 integrins? Results: Natalizumab binds the ␣4 ␤-propeller domain outside the ligand binding groove for domain 1 of vascular cell adhesion molecule (VCAM) and non-competitively antagonizes binding. Conclusion: Natalizumab may push domain 2 of VCAM into a non-preferred orientation upon integrin binding. Significance: Positioning of species-specific substitutions outside of ligand-binding sites leads to surprising antibody mechanisms of action.

Glycosylation and oligomeric state of envelope protein might influence HIV-1 virion capture by α4β7 integrin

“…This was consistently observed for all the scaffolded V1V2 and gp140 constructs tested in this study (see below). X-ray structures of α4β7-Ab complexes have established that Act-1 recognizes the β7 subunit and sterically inhibits the binding of MAdCAM-1 whereas HP2/1 recognizes the α4 subunit with its epitope located on the opposite side of the α4β7 binding cleft (Yu, Schurpf, & Springer, 2013). This suggests that while both MAdCAM-1 and V1V2 domain interacted with α4β7, they did so in a different manner.…”

Structural determinants of integrin β-subunit specificity for latent TGF-β

“…33. In brief, the α V headpiece (residues 1–594) with the M400C mutation was followed by a 3C protease site, the ACID coiled coil, a strep II tag and a histidine tag.…”

Metal ion and ligand binding of integrin α 5 β 1

“…α 5 β 1 headpiece structures with (12) and without (here) the α-subunit thigh domain show no significant difference in the adjacent α-subunit β-propeller domain (0.29-Å rmsd over 402 Cα atoms). The thigh domain in integrins shows considerable flexibility at its interface with the β-propeller domain (20,21,25,29). The hybrid, PSI, and EGF1 domains come much closer to the thigh domain in the closed than open headpiece conformation (Fig.…”