5nsg

Fc DEDE homodimer variant

spinqualitylabelsall models 5nsg, resolution 2.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5nsg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.22Å Ligands: ACT, BMA, FUC, MAN, NAG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q6MZV7_HUMAN Publication Abstract from PubMed Bispecific antibodies combine two different antigen-binding sites in a single molecule, enabling more specific targeting, novel mechanisms of action, and higher clinical efficacies. Although they have the potential to outperform conventional monoclonal antibodies, many bispecific antibodies have issues regarding production, stability, and pharmacokinetic properties. Here, we describe a new approach for generating bispecific antibodies using a common light chain format and exploiting the stable architecture of human immunoglobulin G1 We used iterative experimental validation and computational modeling to identify multiple Fc variant pairs that drive efficient heterodimerization of the antibody heavy chains. Accelerated stability studies enabled selection of one Fc variant pair dubbed "DEKK" consisting of substitutions L351D and L368E in one heavy chain combined with L351K and T366K in the other. Solving the crystal structure of the DEKK Fc region at a resolution of 2.3 A enabled detailed analysis of the interactions inducing CH3 interface heterodimerization. Local shifts in the IgG backbone accommodate the introduction of lysine side chains that form stabilizing salt-bridge interactions with substituted and native residues in the opposite chain. Overall, the CH3 domain adapted to these shifts at the interface, yielding a stable Fc conformation very similar to that in wild-type IgG. Using the DEKK format, we generated the bispecific antibody MCLA-128, targeting human EGF receptors 2 and 3. MCLA-128 could be readily produced and purified at industrial scale with a standard mammalian cell culture platform and a routine purification protocol. Long-term accelerated stability assays confirmed that MCLA-128 is highly stable and has excellent biophysical characteristics. A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1.,De Nardis C, Hendriks LJA, Poirier E, Arvinte T, Gros P, Bakker ABH, de Kruif J J Biol Chem. 2017 Sep 1;292(35):14706-14717. doi: 10.1074/jbc.M117.793497. Epub, 2017 Jun 27. PMID:28655766 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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