View source for 6eup


==Crystal structure of Neisseria meningitidis NadA variant 3 double mutant A33I-I38L==
<StructureSection load='6eup' size='340' side='right'caption='[[6eup]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6eup]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Neisseria_meningitidis Neisseria meningitidis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EUP FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=6eup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eup OCA], [https://pdbe.org/6eup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eup RCSB], [https://www.ebi.ac.uk/pdbsum/6eup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eup ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NADA3_NEIMI NADA3_NEIMI] Adheres to and induces bacterial uptake by human epithelial cells in a microfilament-dependent process. Binding is reduced by pronase treatment, suggesting there is a protein receptor on the human cells (PubMed:15660996, PubMed:30327444). Possible human protein receptors include integrin beta-1 (ITGB1) and oxidized low-density lipoprotein receptor 1 (OLR1) (Probable). Binds to extracellular human Hsp90 (preferentially the beta isoform, HSP90AB1) on monocytes, binding stimulates monocytes in a TLR4-dependent fashion, polymixin B, which binds NadA, blocks the activation. Hsp90 is probably not the first receptor on human monocytes (PubMed:21949862). Non-membrane anchored protein (residues 24-350) is internalized into human epithelial cells by hijacking the endosome recycling pathway and may be recycled back to the cell surface, which might aid transcellular trafficking of the bacteria (PubMed:25347845). A bacterial cell surface protein; antisera against this protein induce complement-mediated killing of this and other strains (PubMed:12045242).<ref>PMID:12045242</ref> <ref>PMID:15660996</ref> <ref>PMID:21949862</ref> <ref>PMID:25347845</ref> <ref>PMID:30327444</ref> <ref>PMID:27302108</ref> 
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== Publication Abstract from PubMed ==
Neisseria meningitidis serogroup B (MenB) is a major cause of sepsis and invasive meningococcal disease. A multicomponent vaccine, 4CMenB, is approved for protection against MenB. Neisserial adhesin A (NadA) is one of the main vaccine antigens, acts in host cell adhesion, and may influence colonization and invasion. Six major genetic variants of NadA exist and can be classified into immunologically distinct groups I and II. Knowledge of the crystal structure of the 4CMenB vaccine component NadA3 (group I) would improve understanding of its immunogenicity, folding, and functional properties and might aid antigen design. Here, X-ray crystallography, biochemical, and cellular studies were used to deeply characterize NadA3. The NadA3 crystal structure is reported; it revealed two unexpected regions of undecad coiled-coil motifs and other conformational differences from NadA5 (group II) not predicted by previous analyses. Structure-guided engineering was performed to increase NadA3 thermostability, and a second crystal structure confirmed the improved packing. Functional NadA3 residues mediating interactions with human receptor LOX-1 were identified. Also, for two protective vaccine-elicited human monoclonal antibodies (5D11, 12H11), we mapped key NadA3 epitopes. These vaccine-elicited human MAbs competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. The data presented provide a significant advance in the understanding of the structure, immunogenicity and function of NadA, one of the main antigens of the multicomponent meningococcus B vaccine.IMPORTANCE The bacterial microbe Neisseria meningitidis serogroup B (MenB) is a major cause of devastating meningococcal disease. An approved multicomponent vaccine, 4CMenB, protects against MenB. Neisserial adhesin A (NadA) is a key vaccine antigen and acts in host cell-pathogen interactions. We investigated the 4CMenB vaccine component NadA3 in order to improve the understanding of its immunogenicity, structure, and function and to aid antigen design. We report crystal structures of NadA3, revealing unexpected structural motifs, and other conformational differences from the NadA5 orthologue studied previously. We performed structure-based antigen design to engineer increased NadA3 thermostability. Functional NadA3 residues mediating interactions with the human receptor LOX-1 and vaccine-elicited human antibodies were identified. These antibodies competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. Our data provide a significant advance in the overall understanding of the 4CMenB vaccine antigen NadA.

NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies.,Liguori A, Dello Iacono L, Maruggi G, Benucci B, Merola M, Lo Surdo P, Lopez-Sagaseta J, Pizza M, Malito E, Bottomley MJ MBio. 2018 Oct 16;9(5). pii: mBio.01914-18. doi: 10.1128/mBio.01914-18. PMID:30327444<ref>PMID:30327444</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6eup" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adhesin 3D structures|Adhesin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Neisseria meningitidis]]
[[Category: Bottomley MJ]]
[[Category: Dello Iacono L]]
[[Category: Liguori A]]
[[Category: Malito E]]