2iqa: Difference between revisions

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OCA

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-[[Image:2iqa.jpg|left|200px]]<br /><applet load="2iqa" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2iqa, resolution 2.000&Aring;" />
-'''PFA2 FAB fragment, monoclinic apo form'''<br />
-==Overview==
+==PFA2 FAB fragment, monoclinic apo form==
-Amyloid aggregates of the amyloid-beta (Abeta) peptide are implicated in, the pathology of Alzheimer's disease. Anti-Abeta monoclonal antibodies, (mAbs) have been shown to reduce amyloid plaques in vitro and in animal, studies. Consequently, passive immunization is being considered for, treating Alzheimer's, and anti-Abeta mAbs are now in phase II trials. We, report the isolation of two mAbs (PFA1 and PFA2) that recognize Abeta, monomers, protofibrils, and fibrils and the structures of their antigen, binding fragments (Fabs) in complex with the Abeta(1-8) peptide DAEFRHDS., The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and, hydrophobic contacts, including interactions with a striking WWDDD motif, of the antigen binding fragments. We also show that a similar sequence, (AKFRHD) derived from the human protein GRIP1 is able to cross-react with, both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an, identical conformation to Abeta(1-8). Because such cross-reactivity has, implications for potential side effects of immunotherapy, our structures, provide a template for designing derivative mAbs that target Abeta with, improved specificity and higher affinity.
+<StructureSection load='2iqa' size='340' side='right'caption='[[2iqa]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2iqa]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IQA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IQA 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&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACM:ACETAMIDE'>ACM</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=2iqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iqa OCA], [https://pdbe.org/2iqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iqa RCSB], [https://www.ebi.ac.uk/pdbsum/2iqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iqa ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/A2NHM3_MOUSE A2NHM3_MOUSE]
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/iq/2iqa_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=2iqa ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Amyloid aggregates of the amyloid-beta (Abeta) peptide are implicated in the pathology of Alzheimer's disease. Anti-Abeta monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-Abeta mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize Abeta monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the Abeta(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to Abeta(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target Abeta with improved specificity and higher affinity.
-==About this Structure==
+Molecular basis for passive immunotherapy of Alzheimer's disease.,Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E, Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. Epub 2007 Sep 25. PMID:17895381<ref>PMID:17895381</ref>
-IQA 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 <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=ACM:'>ACM</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IQA OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-Molecular basis for passive immunotherapy of Alzheimer's disease., Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E, Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C, Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. Epub 2007 Sep 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17895381 17895381]
+</div>
+<div class="pdbe-citations 2iqa" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Antibody 3D structures|Antibody 3D structures]]
+*[[Sandbox 20009|Sandbox 20009]]
+*[[3D structures of non-human antibody|3D structures of non-human antibody]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Mus musculus]]
-[[Category: Protein complex]]
+[[Category: Dealwis C]]
-[[Category: Dealwis, C.]]
+[[Category: Gardberg AS]]
-[[Category: Gardberg, A.S.]]
-[[Category: ACM]]
-[[Category: CL]]
-[[Category: GOL]]
-[[Category: cdr]]
-[[Category: immune system]]
-[[Category: pfa2]]
-[[Category: wwddd]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:59:52 2008''