PDBsum entry 3eo9

Immune system

PDB id: 3eo9

Contents

Protein chains

213 a.a.

214 a.a.

Waters ×625

References listed in PDB file

Key reference

Title

Efalizumab binding to the lfa-1 alphal i domain blocks icam-1 binding via steric hindrance.

Authors

S.Li, H.Wang, B.Peng, M.Zhang, D.Zhang, S.Hou, Y.Guo, J.Ding.

Ref.

Proc Natl Acad Sci U S A, 2009, 106, 4349-4354. [DOI no: 10.1073/pnas.0810844106]

PubMed id

19258452

Abstract

Lymphocyte function-associated antigen 1 (LFA-1) plays important roles in immune cell adhesion, trafficking, and activation and is a therapeutic target for the treatment of multiple autoimmune diseases. Efalizumab is one of the most efficacious antibody drugs for treating psoriasis, a very common skin disease, through inhibition of the binding of LFA-1 to the ligand intercellular adhesion molecule 1 (ICAM-1). We report here the crystal structures of the Efalizumab Fab alone and in complex with the LFA-1 alpha(L) I domain, which reveal the molecular mechanism of inhibition of LFA-1 by Efalizumab. The Fab binds with an epitope on the inserted (I) domain that is distinct from the ligand-binding site. Efalizumab binding blocks the binding of LFA-1 to ICAM-1 via steric hindrance between its light chain and ICAM-1 domain 2 and thus inhibits the activities of LFA-1. These results have important implications for the development of improved antibodies and new therapeutic strategies for the treatment of autoimmune diseases.

Figure 2.
Interactions between the Efalizumab Fab and the LFA-1 α[L] I domain. (A) A stereoview showing the interaction interface of the Fab/I domain complex and the relative role of each CDR loop in the interaction with the I domain. (B) An electrostatic potential surface of the Fab at the interaction interface. There are 2 negatively charged surface patches in the paratope to accommodate several important residues of the I domain. Residues of the I domain are shown side chains. The locations of some Fab residues are indicated with white labels for references. (C) A stereoview showing the hydrogen-bonding interactions between the Fab heavy chain and the epitope of the I domain. The Fab residues are colored in green and the I domain residues in magenta. Hydrogen bonds are indicated by dashed lines. (D) Sequence alignment of the I domains of all 9 known α subunit-containing integrins in the region containing the specificity determining residues. Residues corresponding to Lys-197, Lys-200, and His-201 of the LFA-1 α[L] I domain are indicated by blue boxes.

Figure 3.
Inhibition mechanism of LFA-1 by Efalizumab. (A) Structural comparison of the Fab/I domain complex, the ICAM-1/I domain complex, and ICAM-1. The structures of the Fab/I domain complex and the ICAM-1/I domain complex are superimposed on the basis of the I domain, and the structures of ICAM-1 are superimposed on the basis of domain 1 (residues 1–82). The Fab is shown with a surface representation in the same colors as in Fig. 1A. The I domain and ICAM-1 are shown with coiled ribbons. The MIDAS is shown with the position of Zn^2+ by a green ball. The I domain in the Fab/I domain complex is colored in pink and the I domain in the ICAM-1/I domain complex in light blue. ICAM-1 in the ICAM-1/I domain complex (PDB code 1MQ8) is colored in blue (molecule A) and red (molecule B), ICAM-1 in the unliganded form (PDB code 1IAM) in silver, and ICAM-1 in the unliganded form (PDB code 1IC1) in green (molecule A) and magenta (molecule B), respectively. (B) A schematic diagram showing the inhibition mechanism of LFA-1 by Efalizumab. Upon ICAM-1 binding to the α[L] I domain, LFA-1 undergoes conformational changes and thus transforms the integrin from the inactive, bent conformation to the active, extended conformation. Binding of Efalizumab to the LFA-1 α[L] I domain blocks the binding of ICAM-1 via the steric hindrance between the Fab light chain and the ICAM-1 domain 2 and thus inhibits the activities of LFA-1.