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1sm3

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(New page: 200px<br /> <applet load="1sm3" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sm3, resolution 1.95&Aring;" /> '''CRYSTAL STRUCTURE O...)
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[[Image:1sm3.gif|left|200px]]<br />
 
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<applet load="1sm3" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1sm3, resolution 1.95&Aring;" />
 
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'''CRYSTAL STRUCTURE OF THE TUMOR SPECIFIC ANTIBODY SM3 COMPLEX WITH ITS PEPTIDE EPITOPE'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF THE TUMOR SPECIFIC ANTIBODY SM3 COMPLEX WITH ITS PEPTIDE EPITOPE==
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The anti-breast tumour antibody SM3 has a high selectivity in reacting, specifically with carcinoma-associated mucin. SM3 recognises the core, repeating motif (Pro-Asp-Thr-Arg-Pro) of aberrantly glycosylated, epithelial mucin MUC1, and has potential as a therapeutic and diagnostic, tool. Here we report the crystal structure of the Fab fragment of SM3 in, complex with a 13-residue MUC1 peptide antigen, (Thr1P-Ser2P-Ala3P-Pro4P-Asp5P-Thr6P -Arg7P-Pro8P-Ala9P-Pro10P-Gly11P-, Ser12P-Thr13P). The SM3-MUC1 peptide structure was solved by molecular, replacement, and the current model is refined at 1.95 A resolution with an, R-factor of 21.3% and R-free 28.3%. The MUC1 peptide is bound both by, non-polar interactions and hydrogen bonds in an elongated groove in the, antibody-combining site through interactions with Complimentarity, Determining Regions (CDRs), three of the light chain (L1, L2, L3) and two, of the heavy chain (H1 and H3). The conformation of the peptide is mainly, extended with no discernable standard secondary structure. There is a, single non-proline cis-peptide bond in H3, (Val95H-Gly96H-Gln97H-Phe98H-Ala101H-Ty r102H) between Gly96H and Gln97H, which appears to play a role in SM3-peptide antigen interactions, and, represents the first such example within an antibody hypervariable loop., The SM3-MUC1 peptide structure has implications for rational therapeutic, and diagnostic antibody engineering.
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<StructureSection load='1sm3' size='340' side='right'caption='[[1sm3]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1sm3]] is a 3 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=1SM3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SM3 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1sm3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sm3 OCA], [https://pdbe.org/1sm3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1sm3 RCSB], [https://www.ebi.ac.uk/pdbsum/1sm3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1sm3 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/MUC1_HUMAN MUC1_HUMAN] Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes.
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== Function ==
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[https://www.uniprot.org/uniprot/MUC1_HUMAN MUC1_HUMAN] The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.<ref>PMID:9139698</ref> <ref>PMID:11877440</ref> <ref>PMID:14688481</ref> <ref>PMID:15710329</ref> <ref>PMID:16288032</ref> <ref>PMID:15513966</ref> <ref>PMID:17524503</ref> <ref>PMID:17308127</ref> <ref>PMID:16983337</ref> The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.<ref>PMID:9139698</ref> <ref>PMID:11877440</ref> <ref>PMID:14688481</ref> <ref>PMID:15710329</ref> <ref>PMID:16288032</ref> <ref>PMID:15513966</ref> <ref>PMID:17524503</ref> <ref>PMID:17308127</ref> <ref>PMID:16983337</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sm/1sm3_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1sm3 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The anti-breast tumour antibody SM3 has a high selectivity in reacting specifically with carcinoma-associated mucin. SM3 recognises the core repeating motif (Pro-Asp-Thr-Arg-Pro) of aberrantly glycosylated epithelial mucin MUC1, and has potential as a therapeutic and diagnostic tool. Here we report the crystal structure of the Fab fragment of SM3 in complex with a 13-residue MUC1 peptide antigen (Thr1P-Ser2P-Ala3P-Pro4P-Asp5P-Thr6P -Arg7P-Pro8P-Ala9P-Pro10P-Gly11P- Ser12P-Thr13P). The SM3-MUC1 peptide structure was solved by molecular replacement, and the current model is refined at 1.95 A resolution with an R-factor of 21.3% and R-free 28.3%. The MUC1 peptide is bound both by non-polar interactions and hydrogen bonds in an elongated groove in the antibody-combining site through interactions with Complimentarity Determining Regions (CDRs), three of the light chain (L1, L2, L3) and two of the heavy chain (H1 and H3). The conformation of the peptide is mainly extended with no discernable standard secondary structure. There is a single non-proline cis-peptide bond in H3 (Val95H-Gly96H-Gln97H-Phe98H-Ala101H-Ty r102H) between Gly96H and Gln97H, which appears to play a role in SM3-peptide antigen interactions, and represents the first such example within an antibody hypervariable loop. The SM3-MUC1 peptide structure has implications for rational therapeutic and diagnostic antibody engineering.
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==About this Structure==
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Crystal structure at 1.95 A resolution of the breast tumour-specific antibody SM3 complexed with its peptide epitope reveals novel hypervariable loop recognition.,Dokurno P, Bates PA, Band HA, Stewart LM, Lally JM, Burchell JM, Taylor-Papadimitriou J, Snary D, Sternberg MJ, Freemont PS J Mol Biol. 1998 Dec 4;284(3):713-28. PMID:9826510<ref>PMID:9826510</ref>
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1SM3 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with CD and CL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1SM3 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Crystal structure at 1.95 A resolution of the breast tumour-specific antibody SM3 complexed with its peptide epitope reveals novel hypervariable loop recognition., Dokurno P, Bates PA, Band HA, Stewart LM, Lally JM, Burchell JM, Taylor-Papadimitriou J, Snary D, Sternberg MJ, Freemont PS, J Mol Biol. 1998 Dec 4;284(3):713-28. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9826510 9826510]
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</div>
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[[Category: Mus musculus]]
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<div class="pdbe-citations 1sm3" style="background-color:#fffaf0;"></div>
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[[Category: Protein complex]]
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[[Category: Band, H.A.]]
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[[Category: Bates, P.A.]]
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[[Category: Burchell, J.M.]]
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[[Category: Dokurno, P.]]
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[[Category: Freemont, P.S.]]
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[[Category: Lally, J.M.]]
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[[Category: Snary, D.]]
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[[Category: Sternberg, M.J.E.]]
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[[Category: Stewart, L.M.D.]]
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[[Category: Taylor-Papadimitriou, J.]]
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[[Category: CD]]
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[[Category: CL]]
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[[Category: antibody]]
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[[Category: antitumor antibody]]
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[[Category: complex (antibody/peptide epitope)]]
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[[Category: peptide antigen]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:15:26 2007''
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==See Also==
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*[[Antibody 3D structures|Antibody 3D structures]]
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*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
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*[[3D structures of human antibody|3D structures of human antibody]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Mus musculus]]
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[[Category: Band HA]]
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[[Category: Bates PA]]
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[[Category: Burchell JM]]
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[[Category: Dokurno P]]
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[[Category: Freemont PS]]
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[[Category: Lally JM]]
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[[Category: Snary D]]
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[[Category: Sternberg MJE]]
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[[Category: Stewart LMD]]
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[[Category: Taylor-Papadimitriou J]]

Current revision

CRYSTAL STRUCTURE OF THE TUMOR SPECIFIC ANTIBODY SM3 COMPLEX WITH ITS PEPTIDE EPITOPE

PDB ID 1sm3

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