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Structural analysis of bacterial ABC transporter inhibition by an antibody fragment.

Ahuja S, Rougé L, Swem DL, Sudhamsu J, Wu P, Russell SJ, Alexander MK, Tam C, Nishiyama M, Starovasnik MA, Koth CM
Structure 23 713-23 (2015)
Cited: 19 times
EuropePMC logo PMID: 25752540

Abstract

Bacterial ATP-binding cassette (ABC) importers play critical roles in nutrient acquisition and are potential antibacterial targets. However, structural bases for their inhibition are poorly defined. These pathways typically rely on substrate binding proteins (SBPs), which are essential for substrate recognition, delivery, and transporter function. We report the crystal structure of a Staphylococcus aureus SBP for Mn(II), termed MntC, in complex with FabC1, a potent antibody inhibitor of the MntABC pathway. This pathway is essential and highly expressed during S. aureus infection and facilitates the import of Mn(II), a critical cofactor for enzymes that detoxify reactive oxygen species (ROS). Structure-based functional studies indicate that FabC1 sterically blocks a structurally conserved surface of MntC, preventing its interaction with the MntB membrane importer and increasing wild-type S. aureus sensitivity to oxidative stress by more than 10-fold. The results define an SBP blocking mechanism as the basis for ABC importer inhibition by an engineered antibody fragment.

Reviews citing this publication (3)

  1. Protein Crystallography in Vaccine Research and Development. Malito E, Carfi A, Bottomley MJ. Int J Mol Sci 16 13106-13140 (2015)
  2. Chemical and Biological Aspects of Nutritional Immunity-Perspectives for New Anti-Infectives that Target Iron Uptake Systems. Bilitewski U, Blodgett JAV, Duhme-Klair AK, Dallavalle S, Laschat S, Routledge A, Schobert R. Angew Chem Int Ed Engl 56 14360-14382 (2017)
  3. Borreliella burgdorferi Antimicrobial-Tolerant Persistence in Lyme Disease and Posttreatment Lyme Disease Syndromes. Cabello FC, Embers ME, Newman SA, Godfrey HP. mBio 13 e0344021 (2022)

Articles citing this publication (16)

  1. Synthetic single domain antibodies for the conformational trapping of membrane proteins. Zimmermann I, Egloff P, Hutter CA, Arnold FM, Stohler P, Bocquet N, Hug MN, Huber S, Siegrist M, Hetemann L, Gera J, Gmür S, Spies P, Gygax D, Geertsma ER, Dawson RJ, Seeger MA. Elife 7 e34317 (2018)
  2. Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody. Favuzza P, Guffart E, Tamborrini M, Scherer B, Dreyer AM, Rufer AC, Erny J, Hoernschemeyer J, Thoma R, Schmid G, Gsell B, Lamelas A, Benz J, Joseph C, Matile H, Pluschke G, Rudolph MG. Elife 6 e20383 (2017)
  3. Structural basis of omega-3 fatty acid transport across the blood-brain barrier. Cater RJ, Chua GL, Erramilli SK, Keener JE, Choy BC, Tokarz P, Chin CF, Quek DQY, Kloss B, Pepe JG, Parisi G, Wong BH, Clarke OB, Marty MT, Kossiakoff AA, Khelashvili G, Silver DL, Mancia F. Nature 595 315-319 (2021)
  4. High Resolution Mapping of Bactericidal Monoclonal Antibody Binding Epitopes on Staphylococcus aureus Antigen MntC. Gribenko AV, Parris K, Mosyak L, Li S, Handke L, Hawkins JC, Severina E, Matsuka YV, Anderson AS. PLoS Pathog 12 e1005908 (2016)
  5. MntC-Dependent Manganese Transport Is Essential for Staphylococcus aureus Oxidative Stress Resistance and Virulence. Handke LD, Gribenko AV, Timofeyeva Y, Scully IL, Anderson AS. mSphere 3 e00336-18 (2018)
  6. The Staphylococcus aureus ABC-Type Manganese Transporter MntABC Is Critical for Reinitiation of Bacterial Replication Following Exposure to Phagocytic Oxidative Burst. Coady A, Xu M, Phung Q, Cheung TK, Bakalarski C, Alexander MK, Lehar SM, Kim J, Park S, Tan MW, Nishiyama M. PLoS One 10 e0138350 (2015)
  7. Immunisation With Immunodominant Linear B Cell Epitopes Vaccine of Manganese Transport Protein C Confers Protection against Staphylococcus aureus Infection. Yang HJ, Zhang JY, Wei C, Yang LY, Zuo QF, Zhuang Y, Feng YJ, Srinivas S, Zeng H, Zou QM. PLoS One 11 e0149638 (2016)
  8. Structural Basis for Regulation and Specificity of Fructooligosaccharide Import in Streptococcus pneumoniae. Culurgioni S, Harris G, Singh AK, King SJ, Walsh MA. Structure 25 79-93 (2017)
  9. Structural basis of nanobody-mediated blocking of BtuF, the cognate substrate-binding protein of the Escherichia coli vitamin B12 transporter BtuCD. Mireku SA, Sauer MM, Glockshuber R, Locher KP. Sci Rep 7 14296 (2017)
  10. Structural basis of trehalose recycling by the ABC transporter LpqY-SugABC. Liu F, Liang J, Zhang B, Gao Y, Yang X, Hu T, Yang H, Xu W, Guddat LW, Rao Z. Sci Adv 6 eabb9833 (2020)
  11. Multiple Requirements for Rab GTPases in the Development of Drosophila Tracheal Dorsal Branches and Terminal Cells. Best BT, Leptin M. G3 (Bethesda) 10 1099-1112 (2020)
  12. Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram-Negative Pathogen Salmonella by Attenuating Cellular Stress Response. Mandl FA, Kirsch VC, Ugur I, Kunold E, Vomacka J, Fetzer C, Schneider S, Richter K, Fuchs TM, Antes I, Sieber SA. Angew Chem Int Ed Engl 55 14852-14857 (2016)
  13. Zinc sequestration by human calprotectin facilitates manganese binding to the bacterial solute-binding proteins PsaA and MntC. Rosen T, Hadley RC, Bozzi AT, Ocampo D, Shearer J, Nolan EM. Metallomics 14 mfac001 (2022)
  14. Construction of stable membranal CMTM6-PD-L1 full-length complex to evaluate the PD-1/PD-L1-CMTM6 interaction and develop anti-tumor anti-CMTM6 nanobody. Jia XM, Long YR, Yu XL, Chen RQ, Gong LK, Geng Y. Acta Pharmacol Sin 44 1095-1104 (2023)
  15. Essential Metal Uptake in Gram-negative Bacteria: X-ray Fluorescence, Radioisotopes, and Cell Fractionation. Radka CD, Radford LL, Massicano AVF, DeLucas LJ, Lapi SE, Aller SG. J Vis Exp (2018)
  16. S100A12 promotes Mn(II) binding to pneumococcal PsaA and staphylococcal MntC by Zn(II) sequestration. Rosen T, Nolan EM. J Inorg Biochem 233 111862 (2022)


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