3QUH

Structure of heme transport protein IsdH-NEAT3 from S. aureus in complex with Manganese(III)-porphyrin

Summary for 3QUH

• Entry DOI: 10.2210/pdb3quh/pdb
• Related: 3QUG
• Descriptor: Iron-regulated surface determinant protein H, PROTOPORPHYRIN IX CONTAINING MN, GLYCEROL, ... (4 entities in total)
• Functional Keywords: manganese (iii), metalloporphyrin, metal selectivity, neat domain, heme binding, heme transport, heme, hemin, ppix, protoporphyrin ix, cell wall, heme-binding protein
• Biological source: Staphylococcus aureus
• Cellular location: Secreted, cell wall; Peptidoglycan-anchor (Potential): Q931P4
• Total number of polymer chains: 2
• Total formula weight: 30289.36

Authors

Moriwaki, Y.,Caaveiro, J.M.M.,Tsumoto, K. (deposition date: 2011-02-24, release date: 2011-03-30, Last modification date: 2023-11-01)

Primary citation

Moriwaki, Y.,Caaveiro, J.M.M.,Tanaka, Y.,Tsutsumi, H.,Hamachi, I.,Tsumoto, K.
Molecular basis of recognition of antibacterial porphyrins by heme-transporter IsdH-NEAT3 of Staphylococcus aureus.
Biochemistry, 50:7311-7320, 2011

PubMed Abstract: Antibiotic resistance is increasingly seen as a serious problem that threatens public health and erodes our capacity to effectively combat disease. So-called non-iron metalloporhyrins have shown promising antibacterial properties against a number of pathogenic bacteria including Staphylococcus aureus. However, little is known about the molecular mechanism(s) of action of these compounds and in particular how they reach the interior of the bacterial cells. A popular hypothesis indicates that non-iron metalloporphyrins infiltrate into bacterial cells like a "Trojan horse" using heme transport systems. Iron-regulated surface determinant (Isd) is the best characterized heme transport system of S. aureus. Herein we studied the molecular mechanism by which the extracellular heme-receptor IsdH-NEAT3 of Isd recognizes antimicrobial metalloporphyrins. We found that potent antibacterial porphyrins Ga(III)-protoporphyrin IX (PPIX) and Mn(III)-PPIX closely mimicked the properties of the natural ligand heme, namely (i) stable binding to IsdH-NEAT3 with comparable affinities for the receptor, (ii) nearly undistinghuishable three-dimensional structure when complexed with IsdH-NEAT3, and (iii) similar transfer properties to a second receptor IsdA. On the contrary, weaker antibacterial porphyrins Mg(II)-PPIX, Zn(II)-PPIX, and Cu(II)-PPIX were not captured effectively by IsdH-NEAT3 under our experimental conditions and displayed lower affinities. Moreover, reduction of Fe(III)-PPIX to Fe(II)-PPIX with dithionite abrogated stable binding to receptor. These data revealed a clear connection between oxidation state of metal and effective attachment to IsdH-NEAT3. Also, the strong correlation between binding affinity and reported antimicrobial potency suggested that the Isd system may be used by these antibacterial compounds to gain access to the interior of the cells. We hope these results will increase our understanding of Isd system of S. aureus and highlight its biomedical potential to deliver new and more efficient antibacterial treatments.

PubMed: 21797259
DOI: 10.1021/bi200493h

Experimental method

X-RAY DIFFRACTION (2.7 Å)