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6ya7

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Revision as of 06:41, 19 August 2020

Cdc7-Dbf4 bound to an Mcm2-S40 derived bivalent substrate

Structural highlights

6ya7 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:	,
Gene:	CDC7, CDC7L1 (HUMAN), DBF4, ASK, DBF4A, ZDBF1 (HUMAN)
Activity:	DNA helicase, with EC number 3.6.4.12
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CDC7_HUMAN] Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3.^[1] [MCM2_HUMAN] Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for the entry in S phase and for cell division.^[2] [DBF4A_HUMAN] Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.^[3] ^[4] ^[5]

Publication Abstract from PubMed

CDC7 is an essential Ser/Thr kinase that acts upon the replicative helicase throughout the S phase of the cell cycle and is activated by DBF4. Here, we present crystal structures of a highly active human CDC7-DBF4 construct. The structures reveal a zinc-finger domain at the end of the kinase insert 2 that pins the CDC7 activation loop to motif M of DBF4 and the C lobe of CDC7. These interactions lead to ordering of the substrate-binding platform and full opening of the kinase active site. In a co-crystal structure with a mimic of MCM2 Ser40 phosphorylation target, the invariant CDC7 residues Arg373 and Arg380 engage phospho-Ser41 at substrate P+1 position, explaining the selectivity of the S-phase kinase for Ser/Thr residues followed by a pre-phosphorylated or an acidic residue. Our results clarify the role of DBF4 in activation of CDC7 and elucidate the structural basis for recognition of its preferred substrates.

Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase.,Dick SD, Federico S, Hughes SM, Pye VE, O'Reilly N, Cherepanov P Structure. 2020 Jun 5. pii: S0969-2126(20)30179-9. doi:, 10.1016/j.str.2020.05.010. PMID:32521228^[6]

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

References

↑ Montagnoli A, Bosotti R, Villa F, Rialland M, Brotherton D, Mercurio C, Berthelsen J, Santocanale C. Drf1, a novel regulatory subunit for human Cdc7 kinase. EMBO J. 2002 Jun 17;21(12):3171-81. PMID:12065429 doi:http://dx.doi.org/10.1093/emboj/cdf290
↑ Todorov IT, Pepperkok R, Philipova RN, Kearsey SE, Ansorge W, Werner D. A human nuclear protein with sequence homology to a family of early S phase proteins is required for entry into S phase and for cell division. J Cell Sci. 1994 Jan;107 ( Pt 1):253-65. PMID:8175912
↑ Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H. A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells. Mol Cell Biol. 1999 Jul;19(7):5083-95. PMID:10373557
↑ Jiang W, McDonald D, Hope TJ, Hunter T. Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication. EMBO J. 1999 Oct 15;18(20):5703-13. PMID:10523313 doi:http://dx.doi.org/10.1093/emboj/18.20.5703
↑ Tenca P, Brotherton D, Montagnoli A, Rainoldi S, Albanese C, Santocanale C. Cdc7 is an active kinase in human cancer cells undergoing replication stress. J Biol Chem. 2007 Jan 5;282(1):208-15. Epub 2006 Oct 24. PMID:17062569 doi:http://dx.doi.org/10.1074/jbc.M604457200
↑ Dick SD, Federico S, Hughes SM, Pye VE, O'Reilly N, Cherepanov P. Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase. Structure. 2020 Jun 5. pii: S0969-2126(20)30179-9. doi:, 10.1016/j.str.2020.05.010. PMID:32521228 doi:http://dx.doi.org/10.1016/j.str.2020.05.010

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ya7"

@@ Line 1: / Line 1: @@
 ==Cdc7-Dbf4 bound to an Mcm2-S40 derived bivalent substrate==
-<StructureSection load='6ya7' size='340' side='right'caption='[[6ya7]]' scene=''>
+<StructureSection load='6ya7' size='340' side='right'caption='[[6ya7]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YA7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YA7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ya7]] is a 3 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=6YA7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YA7 FirstGlance]. <br>
-</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=6ya7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ya7 OCA], [http://pdbe.org/6ya7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ya7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ya7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ya7 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=7O5:'>7O5</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDC7, CDC7L1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DBF4, ASK, DBF4A, ZDBF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_helicase DNA helicase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.12 3.6.4.12] </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=6ya7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ya7 OCA], [http://pdbe.org/6ya7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ya7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ya7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ya7 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/CDC7_HUMAN CDC7_HUMAN]] Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3.<ref>PMID:12065429</ref>  [[http://www.uniprot.org/uniprot/MCM2_HUMAN MCM2_HUMAN]] Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for the entry in S phase and for cell division.<ref>PMID:8175912</ref>  [[http://www.uniprot.org/uniprot/DBF4A_HUMAN DBF4A_HUMAN]] Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.<ref>PMID:10373557</ref> <ref>PMID:10523313</ref> <ref>PMID:17062569</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+CDC7 is an essential Ser/Thr kinase that acts upon the replicative helicase throughout the S phase of the cell cycle and is activated by DBF4. Here, we present crystal structures of a highly active human CDC7-DBF4 construct. The structures reveal a zinc-finger domain at the end of the kinase insert 2 that pins the CDC7 activation loop to motif M of DBF4 and the C lobe of CDC7. These interactions lead to ordering of the substrate-binding platform and full opening of the kinase active site. In a co-crystal structure with a mimic of MCM2 Ser40 phosphorylation target, the invariant CDC7 residues Arg373 and Arg380 engage phospho-Ser41 at substrate P+1 position, explaining the selectivity of the S-phase kinase for Ser/Thr residues followed by a pre-phosphorylated or an acidic residue. Our results clarify the role of DBF4 in activation of CDC7 and elucidate the structural basis for recognition of its preferred substrates.
+Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase.,Dick SD, Federico S, Hughes SM, Pye VE, O'Reilly N, Cherepanov P Structure. 2020 Jun 5. pii: S0969-2126(20)30179-9. doi:, 10.1016/j.str.2020.05.010. PMID:32521228<ref>PMID:32521228</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6ya7" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: DNA helicase]]
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Cherepanov P]]
+[[Category: Cherepanov, P]]
-[[Category: Dick SD]]
+[[Category: Dick, S D]]
+[[Category: Bivalent substrate]]
+[[Category: Cdc7]]
+[[Category: Cell cycle]]
+[[Category: Dbf4]]
+[[Category: Kinase]]
+[[Category: Transferase]]

6ya7

From Proteopedia

Revision as of 06:41, 19 August 2020

Cdc7-Dbf4 bound to an Mcm2-S40 derived bivalent substrate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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