5I0Q

Structure of human C4b-binding protein alpha chain CCP domains 1 and 2 in complex with the hypervariable region of mutant group A Streptococcus M2 (K65A, N66A) protein

Summary for 5I0Q

• Entry DOI: 10.2210/pdb5i0q/pdb
• Related: 5HYP 5HYT 5HYU 5HZP
• Descriptor: M protein, serotype 2.1, C4b-binding protein alpha chain (3 entities in total)
• Functional Keywords: m protein, complement, streptococcus pyogenes, hypervariable antigen, immune system
• Biological source: Streptococcus pyogenes; More
• Cellular location: Secreted, cell wall ; Peptidoglycan-anchor : P50468; Secreted: P04003
• Total number of polymer chains: 2
• Total formula weight: 26664.72

Authors

Buffalo, C.Z.,Bahn-Suh, A.J.,Ghosh, P. (deposition date: 2016-02-04, release date: 2016-07-20, Last modification date: 2024-10-30)

Primary citation

Buffalo, C.Z.,Bahn-Suh, A.J.,Hirakis, S.P.,Biswas, T.,Amaro, R.E.,Nizet, V.,Ghosh, P.
Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.
Nat Microbiol, 1:16155-16155, 2016

PubMed Abstract: No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M protein HVRs (apparently ∼90%). Such broad recognition is rare, and we discovered a unique mechanism for this through the structure determination of four sequence-diverse M proteins in complexes with C4BP. The structures revealed a uniform and tolerant 'reading head' in C4BP, which detected conserved sequence patterns hidden within hypervariability. Our results open up possibilities for rational therapies that target the M-C4BP interaction, and also inform a path towards vaccine design.

PubMed: 27595425
DOI: 10.1038/nmicrobiol.2016.155

Experimental method

X-RAY DIFFRACTION (2.293 Å)