5fv7

From Proteopedia

(Difference between revisions)

Revision as of 07:38, 6 May 2020

Human Fen1 in complex with an N-hydroxyurea compound

Structural highlights

5fv7 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FEN1_HUMAN] Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.

Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site.,Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA, McWhirter C, Sioberg CL, Molina DM, Abbott WM, Jones CD, Nissink JW, Durant ST, Grasby JA Nat Chem Biol. 2016 Aug 15. doi: 10.1038/nchembio.2148. PMID:27526030^[7]

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

References

↑ Robins P, Pappin DJ, Wood RD, Lindahl T. Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I. J Biol Chem. 1994 Nov 18;269(46):28535-8. PMID:7961795
↑ Shen B, Nolan JP, Sklar LA, Park MS. Essential amino acids for substrate binding and catalysis of human flap endonuclease 1. J Biol Chem. 1996 Apr 19;271(16):9173-6. PMID:8621570
↑ Tom S, Henricksen LA, Bambara RA. Mechanism whereby proliferating cell nuclear antigen stimulates flap endonuclease 1. J Biol Chem. 2000 Apr 7;275(14):10498-505. PMID:10744741
↑ Qiu J, Bimston DN, Partikian A, Shen B. Arginine residues 47 and 70 of human flap endonuclease-1 are involved in DNA substrate interactions and cleavage site determination. J Biol Chem. 2002 Jul 5;277(27):24659-66. Epub 2002 May 1. PMID:11986308 doi:http://dx.doi.org/10.1074/jbc.M111941200
↑ Guo Z, Qian L, Liu R, Dai H, Zhou M, Zheng L, Shen B. Nucleolar localization and dynamic roles of flap endonuclease 1 in ribosomal DNA replication and damage repair. Mol Cell Biol. 2008 Jul;28(13):4310-9. doi: 10.1128/MCB.00200-08. Epub 2008 Apr, 28. PMID:18443037 doi:http://dx.doi.org/10.1128/MCB.00200-08
↑ Guo Z, Zheng L, Xu H, Dai H, Zhou M, Pascua MR, Chen QM, Shen B. Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat Chem Biol. 2010 Oct;6(10):766-73. doi: 10.1038/nchembio.422. Epub 2010 Aug, 22. PMID:20729856 doi:http://dx.doi.org/10.1038/nchembio.422
↑ Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA, McWhirter C, Sioberg CL, Molina DM, Abbott WM, Jones CD, Nissink JW, Durant ST, Grasby JA. Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. Nat Chem Biol. 2016 Aug 15. doi: 10.1038/nchembio.2148. PMID:27526030 doi:http://dx.doi.org/10.1038/nchembio.2148

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5fv7"

@@ Line 1: / Line 1: @@
 ==Human Fen1 in complex with an N-hydroxyurea compound==
-<StructureSection load='5fv7' size='340' side='right' caption='[[5fv7]], [[Resolution|resolution]] 2.84&Aring;' scene=''>
+<StructureSection load='5fv7' size='340' side='right'caption='[[5fv7]], [[Resolution|resolution]] 2.84&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5fv7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FV7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FV7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5fv7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FV7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FV7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=R3Z:1-[(2S)-2,3-DIHYDRO-1,4-BENZODIOXIN-2-YLMETHYL]-3-HYDROXYTHIENO[3,2-D]PYRIMIDINE-2,4(1H,3H)-DIONE'>R3Z</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=R3Z:1-[(2S)-2,3-DIHYDRO-1,4-BENZODIOXIN-2-YLMETHYL]-3-HYDROXYTHIENO[3,2-D]PYRIMIDINE-2,4(1H,3H)-DIONE'>R3Z</scene></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=5fv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fv7 OCA], [http://pdbe.org/5fv7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fv7 RCSB], [http://www.ebi.ac.uk/pdbsum/5fv7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fv7 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fv7 OCA], [http://pdbe.org/5fv7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fv7 RCSB], [http://www.ebi.ac.uk/pdbsum/5fv7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fv7 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 18: @@
 </div>
 <div class="pdbe-citations 5fv7" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Endonuclease 3D structures|Endonuclease 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Abbott, W M]]
 [[Category: Debreczeni, J E]]

5fv7

From Proteopedia

Revision as of 07:38, 6 May 2020

Human Fen1 in complex with an N-hydroxyurea compound

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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