2r0w: Difference between revisions
From Proteopedia
Jump to navigationJump to search
New page: left|200px<br /> <applet load="2r0w" size="450" color="white" frame="true" align="right" spinBox="true" caption="2r0w, resolution 2.503Å" /> '''PFA2 FAB complexed... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2r0w.gif|left|200px]]<br /> | [[Image:2r0w.gif|left|200px]]<br /><applet load="2r0w" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2r0w" size=" | |||
caption="2r0w, resolution 2.503Å" /> | caption="2r0w, resolution 2.503Å" /> | ||
'''PFA2 FAB complexed with Abeta1-8'''<br /> | '''PFA2 FAB complexed with Abeta1-8'''<br /> | ||
| Line 6: | Line 5: | ||
==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. | ||
==About this Structure== | ==About this Structure== | ||
2R0W 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 NA as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2R0W 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=NA:'>NA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R0W OCA]. | ||
==Reference== | ==Reference== | ||
| Line 23: | Line 19: | ||
[[Category: immunoglobulin; alzheimer disease; amyloid]] | [[Category: immunoglobulin; alzheimer disease; amyloid]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:54:12 2008'' | ||
