1mhp: Difference between revisions

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[[Image:1mhp.gif|left|200px]]<br />

[[Image:1mhp.gif|left|200px]]<br /><applet load="1mhp" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="1mhp" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1mhp, resolution 2.8Å" />

'''Crystal structure of a chimeric alpha1 integrin I-domain in complex with the Fab fragment of a humanized neutralizing antibody'''<br />

==Overview==

The alpha1beta1 (VLA-1) integrin is a cell-surface receptor for collagen, and laminin and has been implicated in biological pathways involved in, several pathological processes. These processes may be inhibited by the, monoclonal antibody AQC2, which binds with high affinity to human, alpha1beta1 integrin. To understand the structural basis of the inhibition, we determined the crystal structure of the complex of a chimeric rat/human, I domain of the alpha1beta1 integrin and the Fab fragment of humanized, AQC2 antibody. The structure of the complex shows that the antibody blocks, the collagen binding site of the I domain. An aspartate residue, from the, CDR3 loop of the antibody heavy chain, coordinates the MIDAS metal ion in, a manner similar to that of a glutamate residue from collagen., Substitution of the aspartate residue by alanine or arginine results in, significant reduction of antibody binding affinity. Interestingly, although the mode of metal ion coordination resembles that of the open, conformation, the I domain maintains an overall closed conformation, previously observed only for unliganded I domains.

The alpha1beta1 (VLA-1) integrin is a cell-surface receptor for collagen and laminin and has been implicated in biological pathways involved in several pathological processes. These processes may be inhibited by the monoclonal antibody AQC2, which binds with high affinity to human alpha1beta1 integrin. To understand the structural basis of the inhibition we determined the crystal structure of the complex of a chimeric rat/human I domain of the alpha1beta1 integrin and the Fab fragment of humanized AQC2 antibody. The structure of the complex shows that the antibody blocks the collagen binding site of the I domain. An aspartate residue, from the CDR3 loop of the antibody heavy chain, coordinates the MIDAS metal ion in a manner similar to that of a glutamate residue from collagen. Substitution of the aspartate residue by alanine or arginine results in significant reduction of antibody binding affinity. Interestingly, although the mode of metal ion coordination resembles that of the open conformation, the I domain maintains an overall closed conformation previously observed only for unliganded I domains.

==About this Structure==

1MHP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with MN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1MHP OCA].

1MHP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=MN:'>MN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MHP OCA].

==Reference==

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[[Category: receptor]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Sun Nov 18 09~~:36:~~45 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:55:19 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1mhp.gif|left|200px]]<br />
+[[Image:1mhp.gif|left|200px]]<br /><applet load="1mhp" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1mhp" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1mhp, resolution 2.8&Aring;" />
 '''Crystal structure of a chimeric alpha1 integrin I-domain in complex with the Fab fragment of a humanized neutralizing antibody'''<br />
 ==Overview==
-The alpha1beta1 (VLA-1) integrin is a cell-surface receptor for collagen, and laminin and has been implicated in biological pathways involved in, several pathological processes. These processes may be inhibited by the, monoclonal antibody AQC2, which binds with high affinity to human, alpha1beta1 integrin. To understand the structural basis of the inhibition, we determined the crystal structure of the complex of a chimeric rat/human, I domain of the alpha1beta1 integrin and the Fab fragment of humanized, AQC2 antibody. The structure of the complex shows that the antibody blocks, the collagen binding site of the I domain. An aspartate residue, from the, CDR3 loop of the antibody heavy chain, coordinates the MIDAS metal ion in, a manner similar to that of a glutamate residue from collagen., Substitution of the aspartate residue by alanine or arginine results in, significant reduction of antibody binding affinity. Interestingly, although the mode of metal ion coordination resembles that of the open, conformation, the I domain maintains an overall closed conformation, previously observed only for unliganded I domains.
+The alpha1beta1 (VLA-1) integrin is a cell-surface receptor for collagen and laminin and has been implicated in biological pathways involved in several pathological processes. These processes may be inhibited by the monoclonal antibody AQC2, which binds with high affinity to human alpha1beta1 integrin. To understand the structural basis of the inhibition we determined the crystal structure of the complex of a chimeric rat/human I domain of the alpha1beta1 integrin and the Fab fragment of humanized AQC2 antibody. The structure of the complex shows that the antibody blocks the collagen binding site of the I domain. An aspartate residue, from the CDR3 loop of the antibody heavy chain, coordinates the MIDAS metal ion in a manner similar to that of a glutamate residue from collagen. Substitution of the aspartate residue by alanine or arginine results in significant reduction of antibody binding affinity. Interestingly, although the mode of metal ion coordination resembles that of the open conformation, the I domain maintains an overall closed conformation previously observed only for unliganded I domains.
 ==About this Structure==
-MHP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with MN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1MHP OCA].
+MHP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=MN:'>MN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MHP OCA].
 ==Reference==
@@ Line 26: / Line 25: @@
 [[Category: receptor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 18 09:36:45 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:55:19 2008''