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| | ==Three-dimensional LPS bound structure of VG16KRKP-KYE28.== | | ==Three-dimensional LPS bound structure of VG16KRKP-KYE28.== |
| - | <StructureSection load='6kbo' size='340' side='right'caption='[[6kbo]], [[NMR_Ensembles_of_Models | 15 NMR models]]' scene=''> | + | <StructureSection load='6kbo' size='340' side='right'caption='[[6kbo]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6kbo]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KBO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KBO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6kbo]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dengue_virus Dengue virus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KBO FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6kbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kbo OCA], [http://pdbe.org/6kbo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kbo RCSB], [http://www.ebi.ac.uk/pdbsum/6kbo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kbo ProSAT]</span></td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6kbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kbo OCA], [https://pdbe.org/6kbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kbo RCSB], [https://www.ebi.ac.uk/pdbsum/6kbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kbo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/HEP2_HUMAN HEP2_HUMAN]] Defects in SERPIND1 are the cause of thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:[http://omim.org/entry/612356 612356]]. A hemostatic disorder characterized by a tendency to recurrent thrombosis.<ref>PMID:2647747</ref> <ref>PMID:10391209</ref> <ref>PMID:11204559</ref> <ref>PMID:15337701</ref> | + | [https://www.uniprot.org/uniprot/HEP2_HUMAN HEP2_HUMAN] Defects in SERPIND1 are the cause of thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:[https://omim.org/entry/612356 612356]. A hemostatic disorder characterized by a tendency to recurrent thrombosis.<ref>PMID:2647747</ref> <ref>PMID:10391209</ref> <ref>PMID:11204559</ref> <ref>PMID:15337701</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HEP2_HUMAN HEP2_HUMAN]] Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner.<ref>PMID:1939083</ref> Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.<ref>PMID:1939083</ref> | + | [https://www.uniprot.org/uniprot/HEP2_HUMAN HEP2_HUMAN] Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner.<ref>PMID:1939083</ref> Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.<ref>PMID:1939083</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The recent development of plants that overexpress antimicrobial peptides (AMPs) provides opportunities for controlling plant diseases. Because plants employ a broad-spectrum antimicrobial defense, including those based on AMPs, transgenic modification for AMP overexpression represents a potential way to utilize a defense system already present in plants. Herein, using an array of techniques and approaches, we report on VG16KRKP and KYE28, two antimicrobial peptides, which in combination exhibit synergistic antimicrobial effects against plant pathogens and are resistant against plant proteases. Investigating the structural origin of these synergistic antimicrobial effects with NMR spectroscopy of the complex formed between these two peptides and their mutated analogs, we demonstrate the formation of an unusual peptide complex, characterized by the formation of a bulky hydrophobic hub, stabilized by aromatic zippers. Using three-dimensional structure analyses of the complex in bacterial outer and inner membrane components and when bound to lipopolysaccharide (LPS) or bacterial membrane mimics, we found that this structure is key for elevating antimicrobial potency of the peptide combination. We conclude that the synergistic antimicrobial effects of VG16KRKP and KYE28 arise from the formation of a well-defined amphiphilic dimer in the presence of LPS and also in the cytoplasmic bacterial membrane environment. Together, these findings highlight a new application of solution NMR spectroscopy to solve complex structures to study peptide-peptide interactions, and they underscore the importance of structural insights for elucidating the antimicrobial effects of AMP mixtures. |
| | + | |
| | + | Structural insights into the combinatorial effects of antimicrobial peptides reveal a role of aromatic-aromatic interactions in antibacterial synergism.,Ilyas H, Kim J, Lee D, Malmsten M, Bhunia A J Biol Chem. 2019 Oct 4;294(40):14615-14633. doi: 10.1074/jbc.RA119.009955. Epub , 2019 Aug 5. PMID:31383740<ref>PMID:31383740</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6kbo" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Dengue virus]] |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bhunia, A]] | + | [[Category: Bhunia A]] |
| - | [[Category: Ilyas, H]] | + | [[Category: Ilyas H]] |
| - | [[Category: Antimicrobial peptide]]
| + | |
| - | [[Category: Antimicrobial protein]]
| + | |
| - | [[Category: Bacterial membrane]]
| + | |
| - | [[Category: Nuclear magnetic spectroscopy]]
| + | |
| - | [[Category: Peptide synergism]]
| + | |
| Structural highlights
Disease
HEP2_HUMAN Defects in SERPIND1 are the cause of thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:612356. A hemostatic disorder characterized by a tendency to recurrent thrombosis.[1] [2] [3] [4]
Function
HEP2_HUMAN Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner.[5] Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.[6]
Publication Abstract from PubMed
The recent development of plants that overexpress antimicrobial peptides (AMPs) provides opportunities for controlling plant diseases. Because plants employ a broad-spectrum antimicrobial defense, including those based on AMPs, transgenic modification for AMP overexpression represents a potential way to utilize a defense system already present in plants. Herein, using an array of techniques and approaches, we report on VG16KRKP and KYE28, two antimicrobial peptides, which in combination exhibit synergistic antimicrobial effects against plant pathogens and are resistant against plant proteases. Investigating the structural origin of these synergistic antimicrobial effects with NMR spectroscopy of the complex formed between these two peptides and their mutated analogs, we demonstrate the formation of an unusual peptide complex, characterized by the formation of a bulky hydrophobic hub, stabilized by aromatic zippers. Using three-dimensional structure analyses of the complex in bacterial outer and inner membrane components and when bound to lipopolysaccharide (LPS) or bacterial membrane mimics, we found that this structure is key for elevating antimicrobial potency of the peptide combination. We conclude that the synergistic antimicrobial effects of VG16KRKP and KYE28 arise from the formation of a well-defined amphiphilic dimer in the presence of LPS and also in the cytoplasmic bacterial membrane environment. Together, these findings highlight a new application of solution NMR spectroscopy to solve complex structures to study peptide-peptide interactions, and they underscore the importance of structural insights for elucidating the antimicrobial effects of AMP mixtures.
Structural insights into the combinatorial effects of antimicrobial peptides reveal a role of aromatic-aromatic interactions in antibacterial synergism.,Ilyas H, Kim J, Lee D, Malmsten M, Bhunia A J Biol Chem. 2019 Oct 4;294(40):14615-14633. doi: 10.1074/jbc.RA119.009955. Epub , 2019 Aug 5. PMID:31383740[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Blinder MA, Andersson TR, Abildgaard U, Tollefsen DM. Heparin cofactor IIOslo. Mutation of Arg-189 to His decreases the affinity for dermatan sulfate. J Biol Chem. 1989 Mar 25;264(9):5128-33. PMID:2647747
- ↑ Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999 Jul;22(3):231-8. PMID:10391209 doi:10.1038/10290
- ↑ Kanagawa Y, Shigekiyo T, Aihara K, Akaike M, Azuma H, Matsumoto T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb Haemost. 2001 Jan;85(1):101-7. PMID:11204559
- ↑ Corral J, Aznar J, Gonzalez-Conejero R, Villa P, Minano A, Vaya A, Carrell RW, Huntington JA, Vicente V. Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis. Circulation. 2004 Sep 7;110(10):1303-7. Epub 2004 Aug 30. PMID:15337701 doi:10.1161/01.CIR.0000140763.51679.D9
- ↑ Van Deerlin VM, Tollefsen DM. The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans. J Biol Chem. 1991 Oct 25;266(30):20223-31. PMID:1939083
- ↑ Van Deerlin VM, Tollefsen DM. The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans. J Biol Chem. 1991 Oct 25;266(30):20223-31. PMID:1939083
- ↑ Ilyas H, Kim J, Lee D, Malmsten M, Bhunia A. Structural insights into the combinatorial effects of antimicrobial peptides reveal a role of aromatic-aromatic interactions in antibacterial synergism. J Biol Chem. 2019 Oct 4;294(40):14615-14633. doi: 10.1074/jbc.RA119.009955. Epub , 2019 Aug 5. PMID:31383740 doi:http://dx.doi.org/10.1074/jbc.RA119.009955
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