Structure, dynamics and immunogenicity of a catalytically inactive CXC Chemokine-degrading Protease SpyCEP from Streptococcus pyogenes
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Over 18 million disease cases and half a million deaths worldwide are estimated to be caused annually by Group A Streptococcus. A vaccine to prevent GAS disease is urgently needed. SpyCEP (Streptococcus pyogenes Cell-Envelope Proteinase) is a surface-exposed serine protease that inactivates chemokines, impairing neutrophil recruitment and bacterial clearance, and has shown promising immunogenicity in preclinical models. Although SpyCEP structure has been partially characterized, a more complete and higher resolution understanding of its antigenic features would be desirable prior to large scale manufacturing. To address these gaps and facilitate development of this globally important vaccine, we performed immunogenicity studies with a safety-engineered SpyCEP mutant, and comprehensively characterized its structure by combining X-ray crystallography, NMR spectroscopy and molecular dynamics simulations. We found that the catalytically-inactive SpyCEP antigen conferred protection similar to wild-type SpyCEP in a mouse infection model. Further, a new higher-resolution crystal structure of the inactive SpyCEP mutant provided new insights into this large chemokine protease comprising nine domains derived from two non-covalently linked fragments. NMR spectroscopy and molecular simulation analyses revealed conformational flexibility that is likely important for optimal substrate recognition and overall function. These combined immunogenicity and structural data demonstrate that the full-length SpyCEP inactive mutant is a strong candidate human vaccine antigen. These findings show how a multi-disciplinary study was used to overcome obstacles in the development of a GAS vaccine, an approach applicable to other future vaccine programs. Moreover, the information provided may also facilitate the structure-based discovery of small-molecule therapeutics targeting SpyCEP protease inhibition.
Date Issued
2020-03-13
Date Acceptance
2020-03-06
Citation
Computational and Structural Biotechnology Journal, 2020, 18, pp.650-660
ISSN
2001-0370
Publisher
Research Network of Computational and Structural Biotechnology
Start Page
650
End Page
660
Journal / Book Title
Computational and Structural Biotechnology Journal
Volume
18
Copyright Statement
© 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor
Wellcome Trust
Medical Research Council (MRC)
Identifier
https://www.sciencedirect.com/science/article/pii/S2001037020300076?via%3Dihub
Grant Number
215539/Z/19/Z
MC_PC_12015
Subjects
0103 Numerical and Computational Mathematics
0802 Computation Theory and Mathematics
Publication Status
Published
Date Publish Online
2020-03-13