Sandbox Reserved 963
From Proteopedia
(Difference between revisions)
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The surface area of the Aβ<sub>2-8</sub> structure is 1118 Ų, from which 60% is buried (665 Ų) in the antibody interface. In addition, we note two significant interfaces between Aβ and WO2 : 367 Ų of its surface contacts the heavy chain and 298 Ų contacts the light chain. We notice '''(Table 1)''' that residues in the middle of the Aβ<sub>1-16</sub> structure exhibit lower B-factors than atoms at the N- and C- terminus of the Aβ<sub>1-16</sub> peptide, indicating that they are more flexible (since the B-factor, also called the temperature factor, represents the relative vibrational motion of different parts of a structure and atoms with low B-factors belong to a part of the structure quite rigid whereas atoms with high B-factors generally belong to part of a structure that is very flexible[http://en.wikipedia.org/wiki/Debye%E2%80%93Waller_factor]).[[Image:Table 2.png|frame|center|'''Table 1 :''' Buried Surface Areas (BSAs) and B-factors of Aβ residues contacting WO2<ref>Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.,Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744</ref>]] Phe4 and His6 are completely buried in the Fab interface, each with nearly half of their surface area buried in the V<sub>H</sub> interface and half in the V<sub>L</sub> interface. All other residues are located exclusively at the interface with either the V<sub>H</sub> or the V<sub>L</sub> domains. | The surface area of the Aβ<sub>2-8</sub> structure is 1118 Ų, from which 60% is buried (665 Ų) in the antibody interface. In addition, we note two significant interfaces between Aβ and WO2 : 367 Ų of its surface contacts the heavy chain and 298 Ų contacts the light chain. We notice '''(Table 1)''' that residues in the middle of the Aβ<sub>1-16</sub> structure exhibit lower B-factors than atoms at the N- and C- terminus of the Aβ<sub>1-16</sub> peptide, indicating that they are more flexible (since the B-factor, also called the temperature factor, represents the relative vibrational motion of different parts of a structure and atoms with low B-factors belong to a part of the structure quite rigid whereas atoms with high B-factors generally belong to part of a structure that is very flexible[http://en.wikipedia.org/wiki/Debye%E2%80%93Waller_factor]).[[Image:Table 2.png|frame|center|'''Table 1 :''' Buried Surface Areas (BSAs) and B-factors of Aβ residues contacting WO2<ref>Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.,Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744</ref>]] Phe4 and His6 are completely buried in the Fab interface, each with nearly half of their surface area buried in the V<sub>H</sub> interface and half in the V<sub>L</sub> interface. All other residues are located exclusively at the interface with either the V<sub>H</sub> or the V<sub>L</sub> domains. | ||
| - | Residues of the light chain closely contacting Aβ residues include <scene name='60/604482/His_27/2'>His27(D)L</scene>, Ser27(E)L and <scene name='60/604482/My_first_scene/18'>Tyr32L</scene> from light-chain CDR 1 (L1) and <scene name='60/604482/My_first_scene/7'>Ser92L, Leu93L, Val94L and Leu96L from L3</scene>. | + | Residues of the light chain closely contacting Aβ residues include <scene name='60/604482/His_27/2'>His27(D)L</scene>, <scene name='60/604482/Ser27/2'> Ser27(E)L </scene> and <scene name='60/604482/My_first_scene/18'>Tyr32L</scene> from light-chain CDR 1 (L1) and <scene name='60/604482/My_first_scene/7'>Ser92L, Leu93L, Val94L and Leu96L from L3</scene>. |
All residues from Phe4 to Ser8, except Asp7, make close contact with the WO2 heavy-chain CDRs. Close contacting interface residues include <scene name='60/604482/My_first_scene/8'>His50H, Tyr52H, Asp54H and Asp56H from H2</scene> and <scene name='60/604482/My_first_scene/9'>Tyr100(B)H and Asn100(E)H from H3</scene>. | All residues from Phe4 to Ser8, except Asp7, make close contact with the WO2 heavy-chain CDRs. Close contacting interface residues include <scene name='60/604482/My_first_scene/8'>His50H, Tyr52H, Asp54H and Asp56H from H2</scene> and <scene name='60/604482/My_first_scene/9'>Tyr100(B)H and Asn100(E)H from H3</scene>. | ||
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====Interactions with Glu3==== | ====Interactions with Glu3==== | ||
| - | Hydrogen bond between the side chain of Glu3 and the main-chain amide of Ser27(E)L. Additionally, there are potential salt bridges between the side chain of Glu3 and Nδ1/Nε2 atoms of <scene name='60/604482/His_27/2'>His27(D)L</scene>. | + | Hydrogen bond between the side chain of Glu3 and the main-chain amide of <scene name='60/604482/Ser27/2'> Ser27(E)L </scene> . Additionally, there are potential salt bridges between the side chain of Glu3 and Nδ1/Nε2 atoms of <scene name='60/604482/His_27/2'>His27(D)L</scene>. |
====Interactions with Phe4==== | ====Interactions with Phe4==== | ||
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===Comparison of unliganded and liganded WO2 Fab structures=== | ===Comparison of unliganded and liganded WO2 Fab structures=== | ||
| - | Unliganded and liganded structures '''(Figure 4)''' superimpose very closely with an r.m.s.d. (root-mean-square deviation) of 0.3 Å on all Cα atoms (the r.m.s.d. is the measure of the average distance between the atoms of superimposed proteins[http://en.wikipedia.org/wiki/Root-mean-square_deviation]). Even the '''CDRs of liganded and unliganded states are barely distinguishable'''. Except for some small variations (<1 Å) around Ser27(E)L (L1), <scene name='60/604482/My_first_scene/11'>Lys33H (H1)</scene>, <scene name='60/604482/My_first_scene/16'>Asp54H (H2)</scene> and <scene name='60/604482/My_first_scene/17'>Glu100(C)H (H3)</scene>, there is no substantial change in the CDRs when Aβ binds with WO2. | + | Unliganded and liganded structures '''(Figure 4)''' superimpose very closely with an r.m.s.d. (root-mean-square deviation) of 0.3 Å on all Cα atoms (the r.m.s.d. is the measure of the average distance between the atoms of superimposed proteins[http://en.wikipedia.org/wiki/Root-mean-square_deviation]). Even the '''CDRs of liganded and unliganded states are barely distinguishable'''. Except for some small variations (<1 Å) around <scene name='60/604482/Ser27/2'> Ser27(E)L </scene> (L1), <scene name='60/604482/My_first_scene/11'>Lys33H (H1)</scene>, <scene name='60/604482/My_first_scene/16'>Asp54H (H2)</scene> and <scene name='60/604482/My_first_scene/17'>Glu100(C)H (H3)</scene>, there is no substantial change in the CDRs when Aβ binds with WO2. |
Moreover, thanks to temperature-factors analysis, it appears that CDR H1 is less flexible in the liganded structure.<ref>Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.,Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744</ref> | Moreover, thanks to temperature-factors analysis, it appears that CDR H1 is less flexible in the liganded structure.<ref>Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.,Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744</ref> | ||
[[Image:Fig. 1b.png|frame|'''Figure 4 :''' Representation of Aβ (shown as ball-and-stick) in the WO2 Fab variable domain CDRs after superimposition of their Cα atoms. The unliganded Form A is in yellow and the complex with Aβ<sub>1-16</sub> is in blue<ref>Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.,Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744</ref>]] | [[Image:Fig. 1b.png|frame|'''Figure 4 :''' Representation of Aβ (shown as ball-and-stick) in the WO2 Fab variable domain CDRs after superimposition of their Cα atoms. The unliganded Form A is in yellow and the complex with Aβ<sub>1-16</sub> is in blue<ref>Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.,Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744</ref>]] | ||
Revision as of 00:05, 8 January 2015
Anti-amyloid-beta Fab WO2 (Form A, P212121)
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