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[[Image: | ==Molecular basis of human XPC gene recognition and cleavage by engineered homing endonuclease heterodimers== | ||
<StructureSection load='2vbl' size='340' side='right' caption='[[2vbl]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vbl]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Chlamydomonas_reinhardtii Chlamydomonas reinhardtii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VBL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VBL FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1t9i|1t9i]], [[1u0c|1u0c]], [[1u0d|1u0d]], [[1af5|1af5]], [[1bp7|1bp7]], [[1g9y|1g9y]], [[1g9z|1g9z]], [[1mow|1mow]], [[1n3e|1n3e]], [[1n3f|1n3f]], [[1t9j|1t9j]], [[2vbj|2vbj]], [[2vbn|2vbn]], [[2vbo|2vbo]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vbl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2vbl RCSB], [http://www.ebi.ac.uk/pdbsum/2vbl PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vb/2vbl_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Xeroderma pigmentosum is a monogenic disease characterized by hypersensitivity to ultraviolet light. The cells of xeroderma pigmentosum patients are defective in nucleotide excision repair, limiting their capacity to eliminate ultraviolet-induced DNA damage, and resulting in a strong predisposition to develop skin cancers. The use of rare cutting DNA endonucleases-such as homing endonucleases, also known as meganucleases-constitutes one possible strategy for repairing DNA lesions. Homing endonucleases have emerged as highly specific molecular scalpels that recognize and cleave DNA sites, promoting efficient homologous gene targeting through double-strand-break-induced homologous recombination. Here we describe two engineered heterodimeric derivatives of the homing endonuclease I-CreI, produced by a semi-rational approach. These two molecules-Amel3-Amel4 and Ini3-Ini4-cleave DNA from the human XPC gene (xeroderma pigmentosum group C), in vitro and in vivo. Crystal structures of the I-CreI variants complexed with intact and cleaved XPC target DNA suggest that the mechanism of DNA recognition and cleavage by the engineered homing endonucleases is similar to that of the wild-type I-CreI. Furthermore, these derivatives induced high levels of specific gene targeting in mammalian cells while displaying no obvious genotoxicity. Thus, homing endonucleases can be designed to recognize and cleave the DNA sequences of specific genes, opening up new possibilities for genome engineering and gene therapy in xeroderma pigmentosum patients whose illness can be treated ex vivo. | |||
Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases.,Redondo P, Prieto J, Munoz IG, Alibes A, Stricher F, Serrano L, Cabaniols JP, Daboussi F, Arnould S, Perez C, Duchateau P, Paques F, Blanco FJ, Montoya G Nature. 2008 Nov 6;456(7218):107-11. PMID:18987743<ref>PMID:18987743</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Endonuclease|Endonuclease]] | *[[Endonuclease|Endonuclease]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Chlamydomonas reinhardtii]] | [[Category: Chlamydomonas reinhardtii]] | ||
[[Category: Alibes, A.]] | [[Category: Alibes, A.]] | ||
Revision as of 09:22, 29 September 2014
Molecular basis of human XPC gene recognition and cleavage by engineered homing endonuclease heterodimersMolecular basis of human XPC gene recognition and cleavage by engineered homing endonuclease heterodimers
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedXeroderma pigmentosum is a monogenic disease characterized by hypersensitivity to ultraviolet light. The cells of xeroderma pigmentosum patients are defective in nucleotide excision repair, limiting their capacity to eliminate ultraviolet-induced DNA damage, and resulting in a strong predisposition to develop skin cancers. The use of rare cutting DNA endonucleases-such as homing endonucleases, also known as meganucleases-constitutes one possible strategy for repairing DNA lesions. Homing endonucleases have emerged as highly specific molecular scalpels that recognize and cleave DNA sites, promoting efficient homologous gene targeting through double-strand-break-induced homologous recombination. Here we describe two engineered heterodimeric derivatives of the homing endonuclease I-CreI, produced by a semi-rational approach. These two molecules-Amel3-Amel4 and Ini3-Ini4-cleave DNA from the human XPC gene (xeroderma pigmentosum group C), in vitro and in vivo. Crystal structures of the I-CreI variants complexed with intact and cleaved XPC target DNA suggest that the mechanism of DNA recognition and cleavage by the engineered homing endonucleases is similar to that of the wild-type I-CreI. Furthermore, these derivatives induced high levels of specific gene targeting in mammalian cells while displaying no obvious genotoxicity. Thus, homing endonucleases can be designed to recognize and cleave the DNA sequences of specific genes, opening up new possibilities for genome engineering and gene therapy in xeroderma pigmentosum patients whose illness can be treated ex vivo. Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases.,Redondo P, Prieto J, Munoz IG, Alibes A, Stricher F, Serrano L, Cabaniols JP, Daboussi F, Arnould S, Perez C, Duchateau P, Paques F, Blanco FJ, Montoya G Nature. 2008 Nov 6;456(7218):107-11. PMID:18987743[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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