Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial Pathogen , an Immunoevasive Factor that Interacts with the Human C5a Anaphylatoxin.

The Gram-positive anaerobic human pathogenic bacterium causes most diagnosed cases of bacterial vaginosis as well as opportunistic infections in immunocompromised patients. In addition to its well-established role in carbohydrate metabolism, D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from and have been reported to act as extracellular virulence factors during streptococcal infections. Here, we report the crystal structure of GAPDH from (GAPDH) at 2.19 Å resolution. The refined model has a crystallographic of 22.6%. GAPDH is a homotetramer wherein each subunit is bound to a nicotinamide adenine dinucleotide (NAD) molecule. The GAPDH enzyme fulfills essential glycolytic as well as moonlight (non-glycolytic) functions, both of which might be targets of chemotherapeutic intervention. We report that GAPDH interacts with the human C5a anaphylatoxin and inhibits C5a-specific granulocyte chemotaxis, thereby suggesting the participation of GAPDH in complement-targeted immunoevasion in a context of infection. The availability of high-quality structures of GAPDH and other homologous virulence factors from Gram-positive pathogens is critical for drug discovery programs. In this study, sequence and structural differences between GAPDH and related bacterial and eukaryotic GAPDH enzymes are reported in an effort to understand how to subvert the immunoevasive properties of GAPDH and evaluate the potential of GAPDH as a druggable target.