6P9H

Crystal structure of human anti staphylococcus aureus antibody STAU-281 Fab in complex with IsdB NEAT2 domain

Summary for 6P9H

• Entry DOI: 10.2210/pdb6p9h/pdb
• Descriptor: Iron-regulated heme-iron binding protein, Human anti staphylococcus aureus antibody STAU-281 Fab heavy chain, Human anti staphylococcus aureus antibody STAU-281 Fab light chain, ... (4 entities in total)
• Functional Keywords: iron-regulated surface determinant system, isdb, neat2 domain, antibody, immune system
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 6
• Total formula weight: 122019.09

Authors

Dong, J.,Crowe, J.E. (deposition date: 2019-06-10, release date: 2020-06-17, Last modification date: 2023-10-11)

Primary citation

Bennett, M.R.,Dong, J.,Bombardi, R.G.,Soto, C.,Parrington, H.M.,Nargi, R.S.,Schoeder, C.T.,Nagel, M.B.,Schey, K.L.,Meiler, J.,Skaar, E.P.,Crowe Jr., J.E.
Human V H 1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis.
Mbio, 10:-, 2019

PubMed Abstract: is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of -encoded mAbs blocks heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of -encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against infection. The human pathogen causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region gene-encoded human monoclonal antibodies with the response against IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.

PubMed: 31641091
DOI: 10.1128/mBio.02473-19

Experimental method

X-RAY DIFFRACTION (3.003 Å)