4f9b: Difference between revisions

Revision as of 04:42, 7 October 2022

Human CDC7 kinase in complex with DBF4 and PHA767491

Structural highlights

4f9b is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	0SY, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

CDC7 is a serine/threonine kinase that is essential for the initiation of eukaryotic DNA replication. CDC7 activity is controlled by its activator, DBF4. Here we present crystal structures of human CDC7-DBF4 in complex with a nucleotide or ATP-competing small molecules, revealing the active and inhibited forms of the kinase, respectively. DBF4 wraps around CDC7, burying approximately 6,000 A(2) of hydrophobic molecular surface in a bipartite interface. The effector domain of DBF4, containing conserved motif C, is essential and sufficient to support CDC7 kinase activity by binding to the kinase N-terminal lobe and stabilizing its canonical alphaC helix. DBF4 motif M latches onto the C-terminal lobe of the kinase, acting as a tethering domain. Our results elucidate the structural basis for binding to and activation of CDC7 by DBF4 and provide a framework for the design of more potent and specific CDC7 inhibitors.

Crystal structure of human CDC7 kinase in complex with its activator DBF4.,Hughes S, Elustondo F, Di Fonzo A, Leroux FG, Wong AC, Snijders AP, Matthews SJ, Cherepanov P Nat Struct Mol Biol. 2012 Nov;19(11):1101-7. doi: 10.1038/nsmb.2404. Epub 2012, Oct 14. PMID:23064647^[4]

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

References

↑ 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:https://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:https://dx.doi.org/10.1074/jbc.M604457200
↑ Hughes S, Elustondo F, Di Fonzo A, Leroux FG, Wong AC, Snijders AP, Matthews SJ, Cherepanov P. Crystal structure of human CDC7 kinase in complex with its activator DBF4. Nat Struct Mol Biol. 2012 Nov;19(11):1101-7. doi: 10.1038/nsmb.2404. Epub 2012, Oct 14. PMID:23064647 doi:https://dx.doi.org/10.1038/nsmb.2404

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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:https://dx.doi.org/10.1093/emboj/18.20.5703

[3] 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:https://dx.doi.org/10.1074/jbc.M604457200

[4] Hughes S, Elustondo F, Di Fonzo A, Leroux FG, Wong AC, Snijders AP, Matthews SJ, Cherepanov P. Crystal structure of human CDC7 kinase in complex with its activator DBF4. Nat Struct Mol Biol. 2012 Nov;19(11):1101-7. doi: 10.1038/nsmb.2404. Epub 2012, Oct 14. PMID:23064647 doi:https://dx.doi.org/10.1038/nsmb.2404

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
 ==Human CDC7 kinase in complex with DBF4 and PHA767491==
-<StructureSection load='4f9b' size='340' side='right' caption='[[4f9b]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+<StructureSection load='4f9b' size='340' side='right'caption='[[4f9b]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4f9b]] is a 4 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=4F9B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F9B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4f9b]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F9B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F9B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0SY:2-(PYRIDIN-4-YL)-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE'>0SY</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0SY:2-(PYRIDIN-4-YL)-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE'>0SY</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4f99|4f99]], [[4f9a|4f9a]], [[4f9c|4f9c]]</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=4f9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f9b OCA], [https://pdbe.org/4f9b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f9b RCSB], [https://www.ebi.ac.uk/pdbsum/4f9b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f9b ProSAT]</span></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]), ASK, DBF4, 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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=4f9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f9b OCA], [http://pdbe.org/4f9b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f9b RCSB], [http://www.ebi.ac.uk/pdbsum/4f9b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f9b 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/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>
+[https://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 ==
@@ Line 25: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Large Structures]]
-[[Category: Cherepanov, P]]
+[[Category: Cherepanov P]]
-[[Category: Hughes, S]]
+[[Category: Hughes S]]
-[[Category: Atp-binding]]
-[[Category: Cell cycle]]
-[[Category: Cell division]]
-[[Category: Dbf4-dependent kinase]]
-[[Category: Ddk]]
-[[Category: Mitosis]]
-[[Category: Nucleotide-binding]]
-[[Category: Nucleus]]
-[[Category: Phosphorylation]]
-[[Category: S phase]]
-[[Category: Ser/thr protein kinase]]
-[[Category: Serine/threonine-protein kinase]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]
-[[Category: Zinc-binding]]

4f9b: Difference between revisions

Revision as of 04:42, 7 October 2022

Human CDC7 kinase in complex with DBF4 and PHA767491

Structural highlights

Function

Publication Abstract from PubMed

References

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