3ULS

Crystal structure of Fab12

Summary for 3ULS

• Entry DOI: 10.2210/pdb3uls/pdb
• Related: 3ULU 3ULV
• Descriptor: Fab12 light chain, Fab12 heavy chain (3 entities in total)
• Functional Keywords: toll-like receptor-3, tlr3, innate immunity, immunoglobulin, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 94616.62

Authors

Luo, J.,Gilliland, G.L.,Obmolova, O.,Malia, T.,Teplyakov, A. (deposition date: 2011-11-11, release date: 2012-05-23, Last modification date: 2024-11-06)

Primary citation

Luo, J.,Obmolova, G.,Malia, T.J.,Wu, S.J.,Duffy, K.E.,Marion, J.D.,Bell, J.K.,Ge, P.,Zhou, Z.H.,Teplyakov, A.,Zhao, Y.,Lamb, R.J.,Jordan, J.L.,San Mateo, L.R.,Sweet, R.W.,Gilliland, G.L.
Lateral Clustering of TLR3:dsRNA Signaling Units Revealed by TLR3ecd:3Fabs Quaternary Structure.
J.Mol.Biol., 421:112-124, 2012

PubMed Abstract: Toll-like receptor 3 (TLR3) recognizes dsRNA and initiates an innate immune response through the formation of a signaling unit (SU) composed of one double-stranded RNA (dsRNA) and two TLR3 molecules. We report the crystal structure of human TLR3 ectodomain (TLR3ecd) in a quaternary complex with three neutralizing Fab fragments. Fab15 binds an epitope that overlaps the C-terminal dsRNA binding site and, in biochemical assays, blocks the interaction of TLR3ecd with dsRNA, thus directly antagonizing TLR3 signaling through inhibition of SU formation. In contrast, Fab12 and Fab1068 bind TLR3ecd at sites distinct from the N- and C-terminal regions that interact with dsRNA and do not inhibit minimal SU formation with short dsRNA. Molecular modeling based on the co-structure rationalizes these observations by showing that both Fab12 and Fab1068 prevent lateral clustering of SUs along the length of the dsRNA ligand. This model is further supported by cell-based assay results using dsRNA ligands of lengths that support single and multiple SUs. Thus, their antagonism of TLR3 signaling indicates that lateral clustering of SUs is required for TLR3 signal transduction.

PubMed: 22579623
DOI: 10.1016/j.jmb.2012.05.006

Experimental method

X-RAY DIFFRACTION (2.495 Å)