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==Crystal structure of human exonuclease 1 Exo1 (D173A) in complex with DNA (complex I)==
==Crystal structure of human exonuclease 1 Exo1 (D173A) in complex with DNA (complex I)==
<StructureSection load='3qe9' size='340' side='right' caption='[[3qe9]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
<StructureSection load='3qe9' size='340' side='right'caption='[[3qe9]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3qe9]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QE9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QE9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3qe9]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QE9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QE9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qea|3qea]], [[3qeb|3qeb]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qea|3qea]], [[3qeb|3qeb]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EXO1, EXOI, HEX1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EXO1, EXOI, HEX1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3qe9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qe9 OCA], [http://pdbe.org/3qe9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qe9 RCSB], [http://www.ebi.ac.uk/pdbsum/3qe9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qe9 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qe9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qe9 OCA], [https://pdbe.org/3qe9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qe9 RCSB], [https://www.ebi.ac.uk/pdbsum/3qe9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qe9 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/EXO1_HUMAN EXO1_HUMAN]] 5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.<ref>PMID:10364235</ref> <ref>PMID:10608837</ref> <ref>PMID:11809771</ref> <ref>PMID:11842105</ref> <ref>PMID:12414623</ref> <ref>PMID:12704184</ref> <ref>PMID:14636568</ref> <ref>PMID:14676842</ref> <ref>PMID:15225546</ref> <ref>PMID:15886194</ref> <ref>PMID:16143102</ref> <ref>PMID:9685493</ref>   
[[https://www.uniprot.org/uniprot/EXO1_HUMAN EXO1_HUMAN]] 5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.<ref>PMID:10364235</ref> <ref>PMID:10608837</ref> <ref>PMID:11809771</ref> <ref>PMID:11842105</ref> <ref>PMID:12414623</ref> <ref>PMID:12704184</ref> <ref>PMID:14636568</ref> <ref>PMID:14676842</ref> <ref>PMID:15225546</ref> <ref>PMID:15886194</ref> <ref>PMID:16143102</ref> <ref>PMID:9685493</ref>   
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[Exonuclease|Exonuclease]]
*[[Exonuclease 3D structures|Exonuclease 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Beese, L S]]
[[Category: Beese, L S]]
[[Category: Hast, M A]]
[[Category: Hast, M A]]

Revision as of 09:04, 8 June 2022

Crystal structure of human exonuclease 1 Exo1 (D173A) in complex with DNA (complex I)Crystal structure of human exonuclease 1 Exo1 (D173A) in complex with DNA (complex I)

Structural highlights

3qe9 is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:EXO1, EXOI, HEX1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[EXO1_HUMAN] 5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Publication Abstract from PubMed

Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. We present structures of hExo1 in complex with a DNA substrate, followed by mutagenesis studies, and propose a common mechanism by which this nuclease family recognizes and processes diverse DNA structures. hExo1 induces a sharp bend in the DNA at nicks or gaps. Frayed 5' ends of nicked duplexes resemble flap junctions, unifying the mechanisms of endo- and exonucleolytic processing. Conformational control of a mobile region in the catalytic site suggests a mechanism for allosteric regulation by binding to protein partners. The relative arrangement of substrate binding sites in these enzymes provides an elegant solution to a complex geometrical puzzle of substrate recognition and processing.

Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.,Orans J, McSweeney EA, Iyer RR, Hast MA, Hellinga HW, Modrich P, Beese LS Cell. 2011 Apr 15;145(2):212-23. PMID:21496642[13]

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

See Also

References

  1. ↑ Qiu J, Qian Y, Chen V, Guan MX, Shen B. Human exonuclease 1 functionally complements its yeast homologues in DNA recombination, RNA primer removal, and mutation avoidance. J Biol Chem. 1999 Jun 18;274(25):17893-900. PMID:10364235
  2. ↑ Lee BI, Wilson DM 3rd. The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities. J Biol Chem. 1999 Dec 31;274(53):37763-9. PMID:10608837
  3. ↑ Genschel J, Bazemore LR, Modrich P. Human exonuclease I is required for 5' and 3' mismatch repair. J Biol Chem. 2002 Apr 12;277(15):13302-11. Epub 2002 Jan 24. PMID:11809771 doi:http://dx.doi.org/10.1074/jbc.M111854200
  4. ↑ Lee Bi BI, Nguyen LH, Barsky D, Fernandes M, Wilson DM 3rd. Molecular interactions of human Exo1 with DNA. Nucleic Acids Res. 2002 Feb 15;30(4):942-9. PMID:11842105
  5. ↑ Sun X, Zheng L, Shen B. Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome. Cancer Res. 2002 Nov 1;62(21):6026-30. PMID:12414623
  6. ↑ Sharma S, Sommers JA, Driscoll HC, Uzdilla L, Wilson TM, Brosh RM Jr. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. J Biol Chem. 2003 Jun 27;278(26):23487-96. Epub 2003 Apr 18. PMID:12704184 doi:http://dx.doi.org/10.1074/jbc.M212798200
  7. ↑ Genschel J, Modrich P. Mechanism of 5'-directed excision in human mismatch repair. Mol Cell. 2003 Nov;12(5):1077-86. PMID:14636568
  8. ↑ Nielsen FC, Jager AC, Lutzen A, Bundgaard JR, Rasmussen LJ. Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA. Oncogene. 2004 Feb 19;23(7):1457-68. PMID:14676842 doi:http://dx.doi.org/10.1038/sj.onc.1207265
  9. ↑ Dzantiev L, Constantin N, Genschel J, Iyer RR, Burgers PM, Modrich P. A defined human system that supports bidirectional mismatch-provoked excision. Mol Cell. 2004 Jul 2;15(1):31-41. PMID:15225546 doi:http://dx.doi.org/10.1016/j.molcel.2004.06.016
  10. ↑ Doherty KM, Sharma S, Uzdilla LA, Wilson TM, Cui S, Vindigni A, Brosh RM Jr. RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination. J Biol Chem. 2005 Jul 29;280(30):28085-94. Epub 2005 May 9. PMID:15886194 doi:http://dx.doi.org/10.1074/jbc.M500265200
  11. ↑ Zhang Y, Yuan F, Presnell SR, Tian K, Gao Y, Tomkinson AE, Gu L, Li GM. Reconstitution of 5'-directed human mismatch repair in a purified system. Cell. 2005 Sep 9;122(5):693-705. PMID:16143102 doi:http://dx.doi.org/10.1016/j.cell.2005.06.027
  12. ↑ Wilson DM 3rd, Carney JP, Coleman MA, Adamson AW, Christensen M, Lamerdin JE. Hex1: a new human Rad2 nuclease family member with homology to yeast exonuclease 1. Nucleic Acids Res. 1998 Aug 15;26(16):3762-8. PMID:9685493
  13. ↑ Orans J, McSweeney EA, Iyer RR, Hast MA, Hellinga HW, Modrich P, Beese LS. Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family. Cell. 2011 Apr 15;145(2):212-23. PMID:21496642 doi:10.1016/j.cell.2011.03.005

3qe9, resolution 2.51Å

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