7dm1

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crystal structure of the M.tuberculosis phosphate ABC transport receptor PstS-1 in complex with Fab p4-36

Structural highlights

7dm1 is a 6 chain structure with sequence from Homo sapiens and Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Ligands:PO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PSTS1_MYCTU Functions in inorganic phosphate uptake, although probably not the main uptake protein under phosphate starvation (PubMed:15731097, PubMed:20933472). Binds phosphate; probably able to bind both H(2)PO(4)(-) and HPO(4)(2-) (PubMed:8294447, PubMed:12842040). Part of the ABC transporter complex PstSACB involved in phosphate import (Probable).[1] [2] [3] [4] A host TLR2 agonist (toll-like receptor), shown experimentally for human and mouse (PubMed:1906192, PubMed:19362712). Requires both host TLR1 and TLR2 as coreceptors to elicit host response in mouse (TLR6 may also play a role) neither CD14 or CD36 function as accessory receptors (PubMed:19362712). Protein purified from culture filtrate induces host (human) monocytes to produce TNF-alpha, IL-6 and IL-12 p40 (IL12B) via ERK1/2 (MAPK3 and MAPK1) and p38 MAPK pathways; MEK inhibitors U0126 and PD98059 and p38 inhibitor SB203580 block most cytokine production (PubMed:16622205). Host ERK1/2 and p38 MAPK activation is mediated mainly by TLR2, but also partially by TLR4, and unlike the case for lipoprotein LpqH the protein moiety of PstS1 seems to be the antigenic agent (PubMed:16622205). Greater activation of ERK1/2 and p38 MAPK is seen in patients with active pulmonary tuberculosis than in tuberculin-negative patients (PubMed:16622205). Induces apoptosis when incubated with human monocyte-derived macrophages via TLR2 (PubMed:19140873). Protein purified from culture filtrate acts via TLR2 and TLR4 to induce host macrophage (shown for mouse) endoplasmic reticulum stress-mediated apoptosis via MAPK (at least JNK), C-C motif chemokine 2 (MCP-1, Ccl2) and ZC3H12 endoribonucleases (MCPIP, Zc3h12) (PubMed:25544271). Functions as an adhesin, binds to human and mouse macrophages via mannose residues, binds to the mouse macrophage mannose receptor (possibly Mrc1) and mediates bacterial phagocytosis (PubMed:25359607).[5] [6] [7] [8] [9] [10]

Publication Abstract from PubMed

Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduce Mycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170, complexed to PstS1, are determined at 2.1 A and 2.4 A resolution, respectively, to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by 50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.

Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.,Watson A, Li H, Ma B, Weiss R, Bendayan D, Abramovitz L, Ben-Shalom N, Mor M, Pinko E, Bar Oz M, Wang Z, Du F, Lu Y, Rybniker J, Dahan R, Huang H, Barkan D, Xiang Y, Javid B, Freund NT Nat Commun. 2021 Jan 27;12(1):602. doi: 10.1038/s41467-021-20930-0. PMID:33504803[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
11 reviews cite this structure
Impact of antibiotics on the human microbiome and consequences for host health.
Patangia et al. (2022)
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See Also

References

  1. ↑ Vyas NK, Vyas MN, Quiocho FA. Crystal structure of M tuberculosis ABC phosphate transport receptor: specificity and charge compensation dominated by ion-dipole interactions. Structure. 2003 Jul;11(7):765-74. PMID:12842040
  2. ↑ Peirs P, Lefèvre P, Boarbi S, Wang XM, Denis O, Braibant M, Pethe K, Locht C, Huygen K, Content J. Mycobacterium tuberculosis with disruption in genes encoding the phosphate binding proteins PstS1 and PstS2 is deficient in phosphate uptake and demonstrates reduced in vivo virulence. Infect Immun. 2005 Mar;73(3):1898-902. PMID:15731097 doi:10.1128/IAI.73.3.1898-1902.2005
  3. ↑ Vanzembergh F, Peirs P, Lefevre P, Celio N, Mathys V, Content J, Kalai M. Effect of PstS sub-units or PknD deficiency on the survival of Mycobacterium tuberculosis. Tuberculosis (Edinb). 2010 Nov;90(6):338-45. PMID:20933472 doi:10.1016/j.tube.2010.09.004
  4. ↑ Chang Z, Choudhary A, Lathigra R, Quiocho FA. The immunodominant 38-kDa lipoprotein antigen of Mycobacterium tuberculosis is a phosphate-binding protein. J Biol Chem. 1994 Jan 21;269(3):1956-8 PMID:8294447
  5. ↑ Jung SB, Yang CS, Lee JS, Shin AR, Jung SS, Son JW, Harding CV, Kim HJ, Park JK, Paik TH, Song CH, Jo EK. The mycobacterial 38-kilodalton glycolipoprotein antigen activates the mitogen-activated protein kinase pathway and release of proinflammatory cytokines through Toll-like receptors 2 and 4 in human monocytes. Infect Immun. 2006 May;74(5):2686-96. PMID:16622205 doi:10.1128/IAI.74.5.2686-2696.2006
  6. ↑ Young DB, Garbe TR. Lipoprotein antigens of Mycobacterium tuberculosis. Res Microbiol. 1991 Jan;142(1):55-65. PMID:1906192 doi:10.1016/0923-2508(91)90097-t
  7. ↑ Sanchez A, Espinosa P, Esparza MA, Colon M, Bernal G, Mancilla R. Mycobacterium tuberculosis 38-kDa lipoprotein is apoptogenic for human monocyte-derived macrophages. Scand J Immunol. 2009 Jan;69(1):20-8. PMID:19140873 doi:10.1111/j.1365-3083.2008.02193.x
  8. ↑ Drage MG, Pecora ND, Hise AG, Febbraio M, Silverstein RL, Golenbock DT, Boom WH, Harding CV. TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis. Cell Immunol. 2009;258(1):29-37. PMID:19362712 doi:10.1016/j.cellimm.2009.03.008
  9. ↑ Esparza M, Palomares B, Garcia T, Espinosa P, Zenteno E, Mancilla R. PstS-1, the 38-kDa Mycobacterium tuberculosis glycoprotein, is an adhesin, which binds the macrophage mannose receptor and promotes phagocytosis. Scand J Immunol. 2015 Jan;81(1):46-55. doi: 10.1111/sji.12249. PMID:25359607 doi:http://dx.doi.org/10.1111/sji.12249
  10. ↑ Lim YJ, Choi JA, Lee JH, Choi CH, Kim HJ, Song CH. Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress-mediated apoptosis via toll-like receptor 2/4. Apoptosis. 2015 Mar;20(3):358-70. PMID:25544271 doi:10.1007/s10495-014-1080-2
  11. ↑ Watson A, Li H, Ma B, Weiss R, Bendayan D, Abramovitz L, Ben-Shalom N, Mor M, Pinko E, Bar Oz M, Wang Z, Du F, Lu Y, Rybniker J, Dahan R, Huang H, Barkan D, Xiang Y, Javid B, Freund NT. Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis. Nat Commun. 2021 Jan 27;12(1):602. PMID:33504803 doi:10.1038/s41467-021-20930-0

Contents


PDB ID 7dm1

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