6P4C

HyHEL10 Fab carrying four heavy chain mutations (HyHEL10-4x): L4F, Y33H, S56N, and Y58F

Summary for 6P4C

• Entry DOI: 10.2210/pdb6p4c/pdb
• Descriptor: HyHEL10 Fab light chain, HyHEL10 Fab heavy chain, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: hyhel10-4x, hyhel10, fab, lysozyme-binder, immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 48148.95

Authors

Langley, D.B.,Christ, D. (deposition date: 2019-05-27, release date: 2020-05-27, Last modification date: 2024-11-06)

Primary citation

Burnett, D.L.,Schofield, P.,Langley, D.B.,Jackson, J.,Bourne, K.,Wilson, E.,Porebski, B.T.,Buckle, A.M.,Brink, R.,Goodnow, C.C.,Christ, D.
Conformational diversity facilitates antibody mutation trajectories and discrimination between foreign and self-antigens.
Proc.Natl.Acad.Sci.USA, 117:22341-22350, 2020

PubMed Abstract: Conformational diversity and self-cross-reactivity of antigens have been correlated with evasion from neutralizing antibody responses. We utilized single cell B cell sequencing, biolayer interferometry and X-ray crystallography to trace mutation selection pathways where the antibody response must resolve cross-reactivity between foreign and self-proteins bearing near-identical contact surfaces, but differing in conformational flexibility. Recurring antibody mutation trajectories mediate long-range rearrangements of framework (FW) and complementarity determining regions (CDRs) that increase binding site conformational diversity. These antibody mutations decrease affinity for self-antigen 19-fold and increase foreign affinity 67-fold, to yield a more than 1,250-fold increase in binding discrimination. These results demonstrate how conformational diversity in antigen and antibody does not act as a barrier, as previously suggested, but rather facilitates high affinity and high discrimination between foreign and self.

PubMed: 32855302
DOI: 10.1073/pnas.2005102117

Experimental method

X-RAY DIFFRACTION (1.85 Å)