1n5o: Difference between revisions
New page: left|200px<br /> <applet load="1n5o" size="450" color="white" frame="true" align="right" spinBox="true" caption="1n5o, resolution 2.80Å" /> '''Structural conseque... |
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[[Image:1n5o.gif|left|200px]]<br /> | [[Image:1n5o.gif|left|200px]]<br /><applet load="1n5o" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1n5o, resolution 2.80Å" /> | caption="1n5o, resolution 2.80Å" /> | ||
'''Structural consequences of a cancer-causing BRCA1-BRCT missense mutation'''<br /> | '''Structural consequences of a cancer-causing BRCA1-BRCT missense mutation'''<br /> | ||
==Overview== | ==Overview== | ||
The integrity of the carboxyl-terminal BRCT repeat region is critical for | The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1 tumor suppressor function; however, the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well characterized, cancer-associated single amino acid substitution, Met-1775 --> Arg-1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1N5O is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CO and SO4 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1N5O is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CO:'>CO</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N5O OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Glover, J | [[Category: Glover, J N.M.]] | ||
[[Category: Williams, R | [[Category: Williams, R S.]] | ||
[[Category: CO]] | [[Category: CO]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: protein folding]] | [[Category: protein folding]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:02:32 2008'' | ||
Revision as of 15:02, 21 February 2008
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Structural consequences of a cancer-causing BRCA1-BRCT missense mutation
OverviewOverview
The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1 tumor suppressor function; however, the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well characterized, cancer-associated single amino acid substitution, Met-1775 --> Arg-1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein.
DiseaseDisease
Known diseases associated with this structure: Breast cancer-1 OMIM:[113705], Breast-ovarian cancer OMIM:[113705], Ovarian cancer OMIM:[113705], Papillary serous carcinoma of the peritoneum OMIM:[113705]
About this StructureAbout this Structure
1N5O is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structural consequences of a cancer-causing BRCA1-BRCT missense mutation., Williams RS, Glover JN, J Biol Chem. 2003 Jan 24;278(4):2630-5. Epub 2002 Nov 8. PMID:12427738
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