|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of the third fibronectin domain (Fn3) of human ROBO1 in complex with the Fab fragment of murine monoclonal antibody B2212A.== | | ==Crystal structure of the third fibronectin domain (Fn3) of human ROBO1 in complex with the Fab fragment of murine monoclonal antibody B2212A.== |
| - | <StructureSection load='3wih' size='340' side='right' caption='[[3wih]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='3wih' size='340' side='right'caption='[[3wih]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3wih]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WIH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WIH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3wih]] is a 6 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=3WIH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WIH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.701Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wii|3wii]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DUTT1, ROBO1, Roundabout homolog 1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3wih FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wih OCA], [https://pdbe.org/3wih PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wih RCSB], [https://www.ebi.ac.uk/pdbsum/3wih PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wih ProSAT]</span></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=3wih FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wih OCA], [http://pdbe.org/3wih PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wih RCSB], [http://www.ebi.ac.uk/pdbsum/3wih PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wih ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ROBO1_HUMAN ROBO1_HUMAN]] Receptor for SLIT1 and SLIT2 which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development. In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex. May be required for lung development.<ref>PMID:10102268</ref> | + | [https://www.uniprot.org/uniprot/ROBO1_HUMAN ROBO1_HUMAN] Receptor for SLIT1 and SLIT2 which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development. In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex. May be required for lung development.<ref>PMID:10102268</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 3wih" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3wih" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Fujitani, H]] | + | [[Category: Fujitani H]] |
| - | [[Category: Hamakubo, T]] | + | [[Category: Hamakubo T]] |
| - | [[Category: Inoue, T]] | + | [[Category: Inoue T]] |
| - | [[Category: Iwanari, H]] | + | [[Category: Iwanari H]] |
| - | [[Category: Kado, Y]] | + | [[Category: Kado Y]] |
| - | [[Category: Kodama, T]] | + | [[Category: Kodama T]] |
| - | [[Category: Mizohata, E]] | + | [[Category: Mizohata E]] |
| - | [[Category: Mochizuki, Y]] | + | [[Category: Mochizuki Y]] |
| - | [[Category: Nagatoishi, M]] | + | [[Category: Nagatoishi M]] |
| - | [[Category: Nakayama, T]] | + | [[Category: Nakayama T]] |
| - | [[Category: Sato, R]] | + | [[Category: Sato R]] |
| - | [[Category: Tsumoto, K]] | + | [[Category: Tsumoto K]] |
| - | [[Category: Yamashita, T]] | + | [[Category: Yamashita T]] |
| - | [[Category: Yokota, Y]] | + | [[Category: Yokota Y]] |
| - | [[Category: Angiogenesis]]
| + | |
| - | [[Category: Fibronectin type-iii domain]]
| + | |
| - | [[Category: Hepatocellular carcinoma antigen]]
| + | |
| - | [[Category: Immune system]]
| + | |
| Structural highlights
Function
ROBO1_HUMAN Receptor for SLIT1 and SLIT2 which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development. In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex. May be required for lung development.[1]
Publication Abstract from PubMed
ROBO1, fibronectin Type-III domain (Fn)-containing protein, is a novel immunotherapeutic target for hepatocellular carcinoma in humans. The crystal structure of the antigen-binding fragment (Fab) of B2212A, the monoclonal antibody against the third Fn domain (Fn3) of ROBO1, was determined in pursuit of antibody drug for hepatocellular carcinoma. This effort was conducted in the presence or absence of the antigen, with the chemical features being investigated by determining the affinity of the antibody using molecular dynamics (MD) and thermodynamics. The structural comparison of B2212A Fab between the complex and the free form revealed that the interfacial Tyr(L) 50 (superscripts L, H, and F stand for the residues in the light chain, heavy chain, and Fn3, respectively) played important roles in Fn3 recognition. That is, the aromatic ring of Tyr(L) 50 pivoted toward Phe(F) 68, forming a CH/pi interaction and a new hydrogen bond with the carbonyl O atom of Phe(F) 68. MD simulations predicted that the Tyr(L) 50-Phe(F) 68 interaction almost entirely dominated Fab-Fn3 binding, and Ala-substitution of Tyr(L) 50 led to a reduced binding of the resultant complex. On the contrary, isothermal titration calorimetry experiments underscored that Ala-substitution of Tyr(L) 50 caused an increase of the binding enthalpy between B2212A and Fn3, but importantly, it induced an increase of the binding entropy, resulting in a suppression of loss in the Gibbs free energy in total. These results suggest that mutation analysis considering the binding entropy as well as the binding enthalpy will aid in the development of novel antibody drugs for hepatocellular carcinoma.
Structural features of interfacial tyrosine residue in ROBO1 fibronectin domain-antibody complex: Crystallographic, thermodynamic, and molecular dynamic analyses.,Nakayama T, Mizohata E, Yamashita T, Nagatoishi S, Nakakido M, Iwanari H, Mochizuki Y, Kado Y, Yokota Y, Satoh R, Tsumoto K, Fujitani H, Kodama T, Hamakubo T, Inoue T Protein Sci. 2015 Mar;24(3):328-40. doi: 10.1002/pro.2619. Epub 2015 Jan 13. PMID:25492858[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, Tessier-Lavigne M, Kidd T. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell. 1999 Mar 19;96(6):795-806. PMID:10102268
- ↑ Nakayama T, Mizohata E, Yamashita T, Nagatoishi S, Nakakido M, Iwanari H, Mochizuki Y, Kado Y, Yokota Y, Satoh R, Tsumoto K, Fujitani H, Kodama T, Hamakubo T, Inoue T. Structural features of interfacial tyrosine residue in ROBO1 fibronectin domain-antibody complex: Crystallographic, thermodynamic, and molecular dynamic analyses. Protein Sci. 2015 Mar;24(3):328-40. doi: 10.1002/pro.2619. Epub 2015 Jan 13. PMID:25492858 doi:http://dx.doi.org/10.1002/pro.2619
|
