6DZR

Crystal structure of h38C2 K99R mutation

Summary for 6DZR

• Entry DOI: 10.2210/pdb6dzr/pdb
• Descriptor: h38c2 heavy chain, h38c2 light chain, CITRATE ANION, ... (5 entities in total)
• Functional Keywords: antibody, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 48048.39

Authors

Park, H.,Rader, C. (deposition date: 2018-07-05, release date: 2019-07-10, Last modification date: 2024-10-16)

Primary citation

Hwang, D.,Nilchan, N.,Nanna, A.R.,Li, X.,Cameron, M.D.,Roush, W.R.,Park, H.,Rader, C.
Site-Selective Antibody Functionalization via Orthogonally Reactive Arginine and Lysine Residues.
Cell Chem Biol, 26:1229-1239.e9, 2019

PubMed Abstract: Homogeneous antibody-drug conjugates (ADCs) that use a highly reactive buried lysine (Lys) residue embedded in a dual variable domain (DVD)-IgG1 format can be assembled with high precision and efficiency under mild conditions. Here we show that replacing the Lys with an arginine (Arg) residue affords an orthogonal ADC assembly that is site-selective and stable. X-ray crystallography confirmed the location of the reactive Arg residue at the bottom of a deep pocket. As the Lys-to-Arg mutation is confined to a single residue in the heavy chain of the DVD-IgG1, heterodimeric assemblies that combine a buried Lys in one arm, a buried Arg in the other arm, and identical light chains, are readily assembled. Furthermore, the orthogonal conjugation chemistry enables the loading of heterodimeric DVD-IgG1s with two different cargos in a one-pot reaction and thus affords a convenient platform for dual-warhead ADCs and other multifaceted antibody conjugates.

PubMed: 31231031
DOI: 10.1016/j.chembiol.2019.05.010

Experimental method

X-RAY DIFFRACTION (2.4 Å)