EM Structure of the Ectodomain of Integrin CD11b/CD18 and Localization of Its Ligand-Binding Site Relative to the Plasma Membrane

Three-dimensional EM structure of the ectodomain of integrin αVβ3 in a complex with fibronectin

Integrins are alphabeta heterodimeric cell surface receptors that mediate transmembrane signaling by binding extracellular and cytoplasmic ligands. The ectodomain of integrin alphaVbeta3 crystallizes in a bent, genuflexed conformation considered to be inactive (unable to bind physiological ligands in solution) unless it is fully extended by activating stimuli. We generated a stable, soluble com...

High-throughput screening based identification of small molecule antagonists of integrin CD11b/CD18 ligand binding.

Binding of leukocyte specific integrin CD11b/CD18 to its physiologic ligands is important for the development of normal immune response in vivo. Integrin CD11b/CD18 is also a key cellular effector of various inflammatory and autoimmune diseases. However, small molecules selectively inhibiting the function of integrin CD11b/CD18 are currently lacking. We used a newly described cell-based high-th...

Identification of novel agonists of the integrin CD11b/CD18.

We report the identification of novel small molecule agonists of integrin CD11b/CD18, which increased, in a dose-dependent manner, the adhesion of the integrin CD11b/CD18 expressing cells to two physiologically relevant ligands: Fibrinogen and iC3b. Compound 6 showed an ex vivo EC(50) of 10.5 microM and in vitro selectivity for binding to the recombinant alphaA-domain of CD11b/CD18. In silico d...

Structure-Based Drug Design Implications for Integrin Regulation and Antibody-Derived Ligand Aspartate: Site in Integrin CD11b/CD18 by an Ion at the Metal Ion-Dependent Adhesion

THE β-TAIL DOMAIN (βTD) REGULATES PHYSIOLOGIC LIGAND BINDING TO INTEGRIN CD11b/CD18

Crystallographic and electron microscopy studies revealed genuflexed (bent) integrins in both unliganded (inactive) and physiologic ligand-bound (active) states, suggesting that local conformational changes are sufficient for activation. Herein we have explored the role of local changes in the contact region between the membrane-proximal β−tail domain (βTD) and the ligand-binding βA domain of t...