PT - JOURNAL ARTICLE AU - Yuan-Ping Pang AU - Marta Casal Moura AU - Gwen E. Thompson AU - Darlene R. Nelson AU - Amber M. Hummel AU - Dieter E. Jenne AU - Daniel Emerling AU - Wayne Volkmuth AU - William H. Robinson AU - Ulrich Specks TI - Remote Activation of a Latent Epitope in an Autoantigen Decoded with Simulated B-Factors AID - 10.1101/559963 DP - 2019 Jan 01 TA - bioRxiv PG - 559963 4099 - http://biorxiv.org/content/early/2019/08/10/559963.short 4100 - http://biorxiv.org/content/early/2019/08/10/559963.full AB - Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103—offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3•ANCA interactions as new GPA treatments.