# Structural basis for heme binding by the Shr protein from Streptococcus pyogenes

## TL;DR

This paper reveals how the Shr protein from Streptococcus pyogenes binds heme, offering insights into bacterial iron acquisition and potential new treatments.

## Contribution

The study provides the first crystal structures of Shr's NEAT domains and identifies methionine residues as key to heme binding in S. pyogenes.

## Key findings

- Crystal structures of Shr's Linker-NEAT1 and NEAT2 domains were determined at 2.35 Å and 2.66 Å resolution.
- Methionine residues are crucial for heme binding in Shr, a feature unique to S. pyogenes heme-binding proteins.
- The findings may inform new therapeutic strategies targeting heme acquisition in S. pyogenes.

## Abstract

Streptococcus pyogenes causes a range of infectious diseases. In an era of increasing antibiotic resistance, new antimicrobial strategies targeting virulence factors, rather than essential survival mechanisms, are being explored. A key virulence factor in S. pyogenes is the bacterial iron acquisition system, because iron is essential but limited in the host due to sequestration by proteins like hemoglobin. The bacteria S. pyogenes possesses the Shr protein that acquires heme from host hemoglobin and transfers it to Shp, a membrane proximity protein. Shr comprises multiple domains, including two NEAr-Transporter (NEAT) domains that directly bind to heme. While structural information of NEAT domains from other bacteria are available, the structure of NEAT domains from Shr remains unknown. In this study, crystal structures of Linker-NEAT1 and NEAT2 domains were determined to 2.35 Å resolution and 2.66 Å resolution, respectively. Structural and mutational analyses revealed that methionine residues play a key role in heme binding, which seems to be a characteristic of heme-binding proteins from S. pyogenes, but not of NEAT domains from other gram-positive species. These findings enhance our understanding of heme acquisition in S. pyogenes and may guide novel therapeutic approaches.