2r0w
From Proteopedia
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|PDB= 2r0w |SIZE=350|CAPTION= <scene name='initialview01'>2r0w</scene>, resolution 2.503Å | |PDB= 2r0w |SIZE=350|CAPTION= <scene name='initialview01'>2r0w</scene>, resolution 2.503Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=NA:SODIUM ION'>NA</scene> | + | |LIGAND= <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2ipt|2IPT]], [[2ipu|2IPU]], [[2iqa|2IQA]], [[2iq9|2IQ9]], [[2r0w|2R0W]], [[2r0z|2R0Z]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r0w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r0w OCA], [http://www.ebi.ac.uk/pdbsum/2r0w PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2r0w RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Alzheimer disease-1, APP-related OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104760 104760]], Amyloidosis, cerebroarterial, Dutch type OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104760 104760]], Amyloidosis, cerebroarterial, Iowa type OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104760 104760]], Blood group, P system OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607922 607922]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Dealwis, C.]] | [[Category: Dealwis, C.]] | ||
[[Category: Gardberg, A S.]] | [[Category: Gardberg, A S.]] | ||
| - | [[Category: | + | [[Category: alzheimer disease]] |
| + | [[Category: amyloid]] | ||
[[Category: immune system]] | [[Category: immune system]] | ||
| - | [[Category: immunoglobulin | + | [[Category: immunoglobulin]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:55:26 2008'' |
Revision as of 01:55, 31 March 2008
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| , resolution 2.503Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Related: | 2IPT, 2IPU, 2IQA, 2IQ9, 2R0W, 2R0Z
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
PFA2 FAB complexed with Abeta1-8
Overview
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
2R0W is a Protein complex structure of sequences from Mus musculus. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Mon Mar 31 04:55:26 2008
