Diabetic foot ulcers(DFUs)are a major diabetic foot complication characterized by persistent biofilms of Staphylococcus aureus and Pseudomonas aeruginosa,mediated by adhesion proteins.This study employed mo-lecular do...Diabetic foot ulcers(DFUs)are a major diabetic foot complication characterized by persistent biofilms of Staphylococcus aureus and Pseudomonas aeruginosa,mediated by adhesion proteins.This study employed mo-lecular docking,molecular dynamics(MD)simulations(100 ns),and MM-GBSA binding free energy calculations to evaluate curcumin's anti-adhesion potential against key S.aureus MSCRAMMs(ClfA,ClfB,FnBPA,Cna,SasG)and P.aeruginosa lectin/biofilm proteins(LecA,PslG,AlgK).Curcumin exhibited favorable docking affinities for FnBPA(7.44 kcal/mol),PslG(7.18 kcal/mol),and ClfA(7.01 kcal/mol),forming hydrogen bonds,hy-drophobic contacts,andπ-stacking interactions within critical adhesion domains.MD simulations confirmed complex stability across 100 ns,with low RMSD fluctuations(1.4-2.8Å)and persistent ligand retention,particularly in the PslG-curcumin complex.MM-GBSA analysis yielded strongly favorable binding free energies:75.10±4.97 kcal/mol(PslG),75.06±4.92 kcal/mol(ClfA),and74.85±5.30 kcal/mol(FnBPA),pre-dominantly driven by van der Waals(50 kcal/mol)and lipophilic(30 kcal/mol)interactions.These findings establish curcumin as a promising multi-target anti-virulence agent that disrupts DFU biofilm adhesion proteins,supporting its potential repurposing for topical delivery formulations for localized wound treatment.展开更多
Staphylococcus aureus is the most important Gram-positive colonizer of human skin and nasal passage,causing high morbidity and mortality.SD-repeat containing protein D(SdrD),an MSCRAMM(Microbial Surface Components Rec...Staphylococcus aureus is the most important Gram-positive colonizer of human skin and nasal passage,causing high morbidity and mortality.SD-repeat containing protein D(SdrD),an MSCRAMM(Microbial Surface Components Recognizing Adhesive Matrix Molecules)family surface protein,plays an important role in S.aureus adhesion and pathogenesis,while its binding target and molecular mechanism remain largely unknown.Here we solved the crystal structures of SdrD N2-N3 domain and N2-N3-B1 domain.Through structural analysis and comparisons,we characterized the ligand binding site of SdrD,and proposed a featured sequence motif of its potential ligands.In addition,the structures revealed for the first time the interactions between B1 domain and N2-N3 domain among B domain-containing MSCRAMMs.Our results may help in understanding the roles SdrD plays in S.aureus adhesion and shed light on the development of novel antibiotics.展开更多
Bone sialoprotein-binding protein （Bbp）, a MSCRAMMs （Microbial Surface Components Recognizing Adhesive Matrix Molecules） family protein expressed on the surface of Staphylococcus aureus （S. aureus）, mediates adh...Bone sialoprotein-binding protein （Bbp）, a MSCRAMMs （Microbial Surface Components Recognizing Adhesive Matrix Molecules） family protein expressed on the surface of Staphylococcus aureus （S. aureus）, mediates adherence to fibrinogen a （Fg a）, a component in the extracellular matrix of the host cell and is important for infection and pathogenesis. In this study, we solved the crystal structures of apo-Bbp273-598 and Bbp273-598-Fg a561-575 complex at a resolution of 2.03 A and 1.45 A, respectively. Apo-Bbp273-598 contained the ligand binding region N2 and N3 domains, both of which followed a DE variant IgG fold characterized by an additional DI strand in N2 domain and D1＇ and D2＇ strands in N3 domain. The peptide mapped to the Fg o561-575 bond to Bbp273-sgs on the open groove between the N2 and N3 domains. Strikingly, the disordered C-terminus in the apo-form reorganized into a highly-ordered loop and a β-strand G＂ covering the ligand upon ligand binding. BbpAla298-Gly301 in the N2 domain of the Bbp273-598-Fg a561-575 complex, which is a loop in the apo-form, formed a short a-helix to interact tightly with the peptide. In addition, Bbpser547-Glns61 in the N3 domain moved toward the binding groove to make contact directly with the peptide, while BbpAsp338-Gly355 and BbpThr365-Tyr387 in N2 domain shifted their configurations to stabilize the reorganized C-terminus mainly through strong hydrogen bonds. Altogether, our results revealed the molecular basis for Bbp-ligand interaction and advanced our understanding of S. aureus infection process.展开更多
基金supported by the National Basic Research Program(973 Program)(Nos.2011CB910502 and 2012CB911101)National Natural Science Foundation of China(Grant Nos.31030020 and 31170679).
文摘Staphylococcus aureus is the most important Gram-positive colonizer of human skin and nasal passage,causing high morbidity and mortality.SD-repeat containing protein D(SdrD),an MSCRAMM(Microbial Surface Components Recognizing Adhesive Matrix Molecules)family surface protein,plays an important role in S.aureus adhesion and pathogenesis,while its binding target and molecular mechanism remain largely unknown.Here we solved the crystal structures of SdrD N2-N3 domain and N2-N3-B1 domain.Through structural analysis and comparisons,we characterized the ligand binding site of SdrD,and proposed a featured sequence motif of its potential ligands.In addition,the structures revealed for the first time the interactions between B1 domain and N2-N3 domain among B domain-containing MSCRAMMs.Our results may help in understanding the roles SdrD plays in S.aureus adhesion and shed light on the development of novel antibiotics.
文摘Bone sialoprotein-binding protein （Bbp）, a MSCRAMMs （Microbial Surface Components Recognizing Adhesive Matrix Molecules） family protein expressed on the surface of Staphylococcus aureus （S. aureus）, mediates adherence to fibrinogen a （Fg a）, a component in the extracellular matrix of the host cell and is important for infection and pathogenesis. In this study, we solved the crystal structures of apo-Bbp273-598 and Bbp273-598-Fg a561-575 complex at a resolution of 2.03 A and 1.45 A, respectively. Apo-Bbp273-598 contained the ligand binding region N2 and N3 domains, both of which followed a DE variant IgG fold characterized by an additional DI strand in N2 domain and D1＇ and D2＇ strands in N3 domain. The peptide mapped to the Fg o561-575 bond to Bbp273-sgs on the open groove between the N2 and N3 domains. Strikingly, the disordered C-terminus in the apo-form reorganized into a highly-ordered loop and a β-strand G＂ covering the ligand upon ligand binding. BbpAla298-Gly301 in the N2 domain of the Bbp273-598-Fg a561-575 complex, which is a loop in the apo-form, formed a short a-helix to interact tightly with the peptide. In addition, Bbpser547-Glns61 in the N3 domain moved toward the binding groove to make contact directly with the peptide, while BbpAsp338-Gly355 and BbpThr365-Tyr387 in N2 domain shifted their configurations to stabilize the reorganized C-terminus mainly through strong hydrogen bonds. Altogether, our results revealed the molecular basis for Bbp-ligand interaction and advanced our understanding of S. aureus infection process.
