2lmq: Difference between revisions

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==Structural Model for a 40-residue Beta-Amyloid Fibril with Three-Fold Symmetry, Negative Stagger==

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<table><tr><td colspan='2'>[[2lmq]] is a 18 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LMQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2LMQ FirstGlance]. <br>

</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2lmn|2lmn]], [[2lmo|2lmo]], [[2lmp|2lmp]]</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=2lmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lmq OCA], [http://pdbe.org/2lmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2lmq RCSB], [http://www.ebi.ac.uk/pdbsum/2lmq PDBsum]</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=2lmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lmq OCA], [http://pdbe.org/2lmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2lmq RCSB], [http://www.ebi.ac.uk/pdbsum/2lmq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2lmq ProSAT]</span></td></tr>

</table>

== Disease ==

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== Publication Abstract from PubMed ==

We describe ~~solid-state nuclear magnetic resonance (NMR) measurements on~~ fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)) ~~that place~~ constraints ~~on the identity~~ and ~~symmetry of contacts between in-register~~, ~~parallel beta~~-~~sheets in~~ the ~~fibrils. We refer to these contacts as internal and external quaternary contacts, depending on whether they are within a single molecular layer or~~ between ~~molecular layers~~. The ~~data include (1) two~~-~~dimensional 13C~~-~~13C NMR spectra that indicate internal quaternary contacts between side chains of L17~~ and ~~F19 and side chains~~ of ~~I32, L34, and V36, as well as external quaternary contacts between side chains~~ of ~~I31 and G37;~~ (2) ~~two-dimensional 15N-13C~~ NMR ~~spectra that indicate external quaternary contacts between the side chain of M35 and the peptide backbone at G33;~~ (3) ~~measurements of magnetic dipole-dipole couplings between~~ the side chain carboxylate group of D23 and the side chain amine group of K28 that indicate salt bridge interactions. Isotopic dilution experiments allow us to make distinctions between intramolecular and intermolecular contacts. On the ~~basis of these data and previously determined structural constraints from solid-state NMR and electron microscopy~~, ~~we construct full molecular models using restrained molecular dynamics simulations and restrained energy minimization. These models apply to~~ Abeta(1-40) ~~fibrils grown with gentle agitation~~. ~~We also present evidence for different internal~~ quaternary contacts in ~~Abeta(1~~-~~40)~~ fibrils ~~grown without agitation~~, ~~which are morphologically distinct~~.

We describe a full structural model for amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)), based on numerous constraints from solid state NMR and electron microscopy. This model applies specifically to fibrils with a periodically twisted morphology, with twist period equal to 120 +/- 20 nm (defined as the distance between apparent minima in fibril width in negatively stained transmission electron microscope images). The structure has threefold symmetry about the fibril growth axis, implied by mass-per-length data and the observation of a single set of (13)C NMR signals. Comparison with a previously reported model for Abeta(1-40) fibrils with a qualitatively different, striated ribbon morphology reveals the molecular basis for polymorphism. At the molecular level, the 2 Abeta(1-40) fibril morphologies differ in overall symmetry (twofold vs. threefold), the conformation of non-beta-strand segments, and certain quaternary contacts. Both morphologies contain in-register parallel beta-sheets, constructed from nearly the same beta-strand segments. Because twisted and striated ribbon morphologies are also observed for amyloid fibrils formed by other polypeptides, such as the amylin peptide associated with type 2 diabetes, these structural variations may have general implications.

~~Experimental constraints on quaternary structure~~ in Alzheimer's beta-amyloid fibrils.,~~Petkova AT~~, Yau WM, Tycko R ~~Biochemistry~~. ~~2006 Jan 17~~;45(2):~~498~~-~~512~~. PMID:~~16401079~~<ref>PMID:~~16401079~~</ref>

Molecular structural basis for polymorphism in Alzheimer's beta-amyloid fibrils.,Paravastu AK, Leapman RD, Yau WM, Tycko R Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18349-54. Epub 2008 Nov 17. PMID:19015532<ref>PMID:19015532</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

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 ==Structural Model for a 40-residue Beta-Amyloid Fibril with Three-Fold Symmetry, Negative Stagger==
 <StructureSection load='2lmq' size='340' side='right' caption='[[2lmq]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[2lmq]] is a 18 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LMQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2LMQ FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2lmn|2lmn]], [[2lmo|2lmo]], [[2lmp|2lmp]]</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=2lmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lmq OCA], [http://pdbe.org/2lmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2lmq RCSB], [http://www.ebi.ac.uk/pdbsum/2lmq PDBsum]</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=2lmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lmq OCA], [http://pdbe.org/2lmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2lmq RCSB], [http://www.ebi.ac.uk/pdbsum/2lmq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2lmq ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 12: / Line 13: @@
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-We describe solid-state nuclear magnetic resonance (NMR) measurements on fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)) that place constraints on the identity and symmetry of contacts between in-register, parallel beta-sheets in the fibrils. We refer to these contacts as internal and external quaternary contacts, depending on whether they are within a single molecular layer or between molecular layers. The data include (1) two-dimensional 13C-13C NMR spectra that indicate internal quaternary contacts between side chains of L17 and F19 and side chains of I32, L34, and V36, as well as external quaternary contacts between side chains of I31 and G37; (2) two-dimensional 15N-13C NMR spectra that indicate external quaternary contacts between the side chain of M35 and the peptide backbone at G33; (3) measurements of magnetic dipole-dipole couplings between the side chain carboxylate group of D23 and the side chain amine group of K28 that indicate salt bridge interactions. Isotopic dilution experiments allow us to make distinctions between intramolecular and intermolecular contacts. On the basis of these data and previously determined structural constraints from solid-state NMR and electron microscopy, we construct full molecular models using restrained molecular dynamics simulations and restrained energy minimization. These models apply to Abeta(1-40) fibrils grown with gentle agitation. We also present evidence for different internal quaternary contacts in Abeta(1-40) fibrils grown without agitation, which are morphologically distinct.
+We describe a full structural model for amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)), based on numerous constraints from solid state NMR and electron microscopy. This model applies specifically to fibrils with a periodically twisted morphology, with twist period equal to 120 +/- 20 nm (defined as the distance between apparent minima in fibril width in negatively stained transmission electron microscope images). The structure has threefold symmetry about the fibril growth axis, implied by mass-per-length data and the observation of a single set of (13)C NMR signals. Comparison with a previously reported model for Abeta(1-40) fibrils with a qualitatively different, striated ribbon morphology reveals the molecular basis for polymorphism. At the molecular level, the 2 Abeta(1-40) fibril morphologies differ in overall symmetry (twofold vs. threefold), the conformation of non-beta-strand segments, and certain quaternary contacts. Both morphologies contain in-register parallel beta-sheets, constructed from nearly the same beta-strand segments. Because twisted and striated ribbon morphologies are also observed for amyloid fibrils formed by other polypeptides, such as the amylin peptide associated with type 2 diabetes, these structural variations may have general implications.
-Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils.,Petkova AT, Yau WM, Tycko R Biochemistry. 2006 Jan 17;45(2):498-512. PMID:16401079<ref>PMID:16401079</ref>
+Molecular structural basis for polymorphism in Alzheimer's beta-amyloid fibrils.,Paravastu AK, Leapman RD, Yau WM, Tycko R Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18349-54. Epub 2008 Nov 17. PMID:19015532<ref>PMID:19015532</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>