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| | ==Crystal structure of the complex of TLR3 and bi-specific diabody== | | ==Crystal structure of the complex of TLR3 and bi-specific diabody== |
| - | <StructureSection load='5gs0' size='340' side='right' caption='[[5gs0]], [[Resolution|resolution]] 3.27Å' scene=''> | + | <StructureSection load='5gs0' size='340' side='right'caption='[[5gs0]], [[Resolution|resolution]] 3.27Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5gs0]] is a 10 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GS0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GS0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5gs0]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GS0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GS0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.275Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5gru|5gru]], [[5grv|5grv]], [[5grw|5grw]], [[5grx|5grx]], [[5gry|5gry]], [[5grz|5grz]], [[5gs1|5gs1]], [[5gs2|5gs2]], [[5gs3|5gs3]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=5gs0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gs0 OCA], [http://pdbe.org/5gs0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gs0 RCSB], [http://www.ebi.ac.uk/pdbsum/5gs0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gs0 ProSAT]</span></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=5gs0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gs0 OCA], [https://pdbe.org/5gs0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gs0 RCSB], [https://www.ebi.ac.uk/pdbsum/5gs0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gs0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TLR3_HUMAN TLR3_HUMAN]] Defects in TLR3 are associated with herpes simplex encephalitis type 2 (HSE2) [MIM:[http://omim.org/entry/613002 613002]]. HSE is a rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=TLR3 mutations predispose otherwise healthy individuals to isolated herpes simplex encephalitis through a mechanism that involves impaired IFNs production and reduced immune defense against viral infection in the central nervous system.<ref>PMID:17872438</ref> | + | [https://www.uniprot.org/uniprot/TLR3_HUMAN TLR3_HUMAN] Defects in TLR3 are associated with herpes simplex encephalitis type 2 (HSE2) [MIM:[https://omim.org/entry/613002 613002]. HSE is a rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=TLR3 mutations predispose otherwise healthy individuals to isolated herpes simplex encephalitis through a mechanism that involves impaired IFNs production and reduced immune defense against viral infection in the central nervous system.<ref>PMID:17872438</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TLR3_HUMAN TLR3_HUMAN]] Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.<ref>PMID:16144834</ref> <ref>PMID:16858407</ref> <ref>PMID:16720699</ref> <ref>PMID:17178723</ref> <ref>PMID:18172197</ref> <ref>PMID:16043704</ref> | + | [https://www.uniprot.org/uniprot/TLR3_HUMAN TLR3_HUMAN] Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.<ref>PMID:16144834</ref> <ref>PMID:16858407</ref> <ref>PMID:16720699</ref> <ref>PMID:17178723</ref> <ref>PMID:18172197</ref> <ref>PMID:16043704</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Building a sophisticated protein nano-assembly requires a method for linking protein components in a predictable and stable structure. Diabodies are engineered antibody fragments that are composed of two Fv domains connected by short peptide linkers. They are attractive candidates for mediators in assembling protein nano-structures because they can simultaneously bind to two different proteins and are rigid enough to be crystallized. However, comparison of previous crystal structures demonstrates that there is substantial structural diversity in the Fv interface region of diabodies and, therefore, reliable prediction of its structure is not trivial. Here, we present the crystal structures of ten mono- and bi-specific diabodies. We found that changing an arginine residue in the Fv interface to threonine greatly reduced the structural diversity of diabodies. We also found that one of the bispecific diabodies underwent an unexpected process of chain swapping yielding a non-functional monospecific diabody. In order to further reduce structural flexibility and prevent chain shuffling, we introduced disulfide bridges in the Fv interface regions. The disulfide-bridged diabodies have rigid and predictable structures and may have applications in crystallizing proteins, analyzing cryo-electron microscopic images and building protein nano-assemblies.
| + | |
| | | | |
| - | Crystal structures of mono- and bi-specific diabodies and reduction of their structural flexibility by introduction of disulfide bridges at the Fv interface.,Kim JH, Song DH, Youn SJ, Kim JW, Cho G, Kim SC, Lee H, Jin MS, Lee JO Sci Rep. 2016 Sep 29;6:34515. doi: 10.1038/srep34515. PMID:27682821<ref>PMID:27682821</ref>
| + | ==See Also== |
| - | | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | *[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]] |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5gs0" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cho, G]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kim, J H]] | + | [[Category: Large Structures]] |
| - | [[Category: Kim, J W]] | + | [[Category: Mus musculus]] |
| - | [[Category: Lee, H]] | + | [[Category: Cho G]] |
| - | [[Category: Lee, J O]] | + | [[Category: Kim JH]] |
| - | [[Category: Song, D H]] | + | [[Category: Kim JW]] |
| - | [[Category: Youn, S J]] | + | [[Category: Lee H]] |
| - | [[Category: Antibody fragment]] | + | [[Category: Lee JO]] |
| - | [[Category: Complex]] | + | [[Category: Song DH]] |
| - | [[Category: Diabody]] | + | [[Category: Youn SJ]] |
| - | [[Category: Immune system]]
| + | |
| Structural highlights
Disease
TLR3_HUMAN Defects in TLR3 are associated with herpes simplex encephalitis type 2 (HSE2) [MIM:613002. HSE is a rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=TLR3 mutations predispose otherwise healthy individuals to isolated herpes simplex encephalitis through a mechanism that involves impaired IFNs production and reduced immune defense against viral infection in the central nervous system.[1]
Function
TLR3_HUMAN Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.[2] [3] [4] [5] [6] [7]
See Also
References
- ↑ Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, Lebon P, Heron B, Vallee L, Quintana-Murci L, Hovnanian A, Rozenberg F, Vivier E, Geissmann F, Tardieu M, Abel L, Casanova JL. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007 Sep 14;317(5844):1522-7. PMID:17872438 doi:317/5844/1522
- ↑ de Bouteiller O, Merck E, Hasan UA, Hubac S, Benguigui B, Trinchieri G, Bates EE, Caux C. Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH. J Biol Chem. 2005 Nov 18;280(46):38133-45. Epub 2005 Sep 6. PMID:16144834 doi:M507163200
- ↑ Johnsen IB, Nguyen TT, Ringdal M, Tryggestad AM, Bakke O, Lien E, Espevik T, Anthonsen MW. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling. EMBO J. 2006 Jul 26;25(14):3335-46. Epub 2006 Jul 6. PMID:16858407 doi:7601222
- ↑ Bell JK, Askins J, Hall PR, Davies DR, Segal DM. The dsRNA binding site of human Toll-like receptor 3. Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8792-7. Epub 2006 May 23. PMID:16720699 doi:10.1073/pnas.0603245103
- ↑ Sarkar SN, Elco CP, Peters KL, Chattopadhyay S, Sen GC. Two tyrosine residues of Toll-like receptor 3 trigger different steps of NF-kappa B activation. J Biol Chem. 2007 Feb 9;282(6):3423-7. Epub 2006 Dec 18. PMID:17178723 doi:C600226200
- ↑ Leonard JN, Ghirlando R, Askins J, Bell JK, Margulies DH, Davies DR, Segal DM. The TLR3 signaling complex forms by cooperative receptor dimerization. Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):258-63. doi: 10.1073/pnas.0710779105., Epub 2008 Jan 2. PMID:18172197 doi:10.1073/pnas.0710779105
- ↑ Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, Davies DR. The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10976-80. Epub 2005 Jul 25. PMID:16043704
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