Imperial College London

DrJamesPease

Faculty of MedicineNational Heart & Lung Institute

Reader in Leukocyte Biology
 
 
 
//

Contact

 

+44 (0)20 7594 3162j.pease Website

 
 
//

Location

 

109Sir Alexander Fleming BuildingSouth Kensington Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Matthews:2020:10.1016/j.csbj.2020.03.004,
author = {Matthews, S and McKenna, S and Malito, E and Rouse, S and Abate, F and Bensi, G and Emiliano, C and Micoli, F and Mancini, F and Gomes, Moriel D and Grandi, G and Mossakowska, D and Pearson, M and Xu, Y and Pease, J and Sriskandan, S and Margarit, I and Bottomley, MJ},
doi = {10.1016/j.csbj.2020.03.004},
journal = {Computational and Structural Biotechnology Journal},
pages = {650--660},
title = {Structure, dynamics and immunogenicity of a catalytically inactive CXC Chemokine-degrading Protease SpyCEP from Streptococcus pyogenes},
url = {http://dx.doi.org/10.1016/j.csbj.2020.03.004},
volume = {18},
year = {2020}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Matthews,S
AU - McKenna,S
AU - Malito,E
AU - Rouse,S
AU - Abate,F
AU - Bensi,G
AU - Emiliano,C
AU - Micoli,F
AU - Mancini,F
AU - Gomes,Moriel D
AU - Grandi,G
AU - Mossakowska,D
AU - Pearson,M
AU - Xu,Y
AU - Pease,J
AU - Sriskandan,S
AU - Margarit,I
AU - Bottomley,MJ
DO - 10.1016/j.csbj.2020.03.004
EP - 660
PY - 2020///
SN - 2001-0370
SP - 650
TI - Structure, dynamics and immunogenicity of a catalytically inactive CXC Chemokine-degrading Protease SpyCEP from Streptococcus pyogenes
T2 - Computational and Structural Biotechnology Journal
UR - http://dx.doi.org/10.1016/j.csbj.2020.03.004
UR - https://www.sciencedirect.com/science/article/pii/S2001037020300076?via%3Dihub
UR - http://hdl.handle.net/10044/1/78264
VL - 18
ER -