|
|
| Line 3: |
Line 3: |
| | <StructureSection load='4rjf' size='340' side='right'caption='[[4rjf]], [[Resolution|resolution]] 2.01Å' scene=''> | | <StructureSection load='4rjf' size='340' side='right'caption='[[4rjf]], [[Resolution|resolution]] 2.01Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rjf]] 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=4RJF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RJF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rjf]] is a 6 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=4RJF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RJF FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PCNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </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=4rjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rjf OCA], [https://pdbe.org/4rjf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rjf RCSB], [https://www.ebi.ac.uk/pdbsum/4rjf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rjf ProSAT]</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=4rjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rjf OCA], [http://pdbe.org/4rjf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rjf RCSB], [http://www.ebi.ac.uk/pdbsum/4rjf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rjf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PCNA_HUMAN PCNA_HUMAN]] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.<ref>PMID:19443450</ref> <ref>PMID:18719106</ref> [[http://www.uniprot.org/uniprot/CDN1A_HUMAN CDN1A_HUMAN]] May be the important intermediate by which p53/TP53 mediates its role as an inhibitor of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex.<ref>PMID:8242751</ref> <ref>PMID:9106657</ref> | + | [https://www.uniprot.org/uniprot/CDN1A_HUMAN CDN1A_HUMAN] May be the important intermediate by which p53/TP53 mediates its role as an inhibitor of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex.<ref>PMID:8242751</ref> <ref>PMID:9106657</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 19: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Proliferating Cell Nuclear Antigen|Proliferating Cell Nuclear Antigen]] | + | *[[Proliferating cell nuclear antigen 3D structures|Proliferating cell nuclear antigen 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bruning, J B]] | + | [[Category: Bruning JB]] |
| - | [[Category: Kroker, A J]] | + | [[Category: Kroker AJ]] |
| - | [[Category: Dna polymerase]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: P21]]
| + | |
| - | [[Category: Processivity factor]]
| + | |
| - | [[Category: Replication]]
| + | |
| - | [[Category: Sliding clamp]]
| + | |
| Structural highlights
Function
CDN1A_HUMAN May be the important intermediate by which p53/TP53 mediates its role as an inhibitor of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex.[1] [2]
Publication Abstract from PubMed
Proliferating cell nuclear antigen (PCNA, processivity factor, sliding clamp) is a ring-shaped protein that tethers proteins to DNA in processes, including DNA replication, DNA repair, and cell-cycle control. Often used as a marker for cell proliferation, PCNA is overexpressed in cancer cells, making it an appealing pharmaceutical target. PCNA interacts with proteins through a PCNA interacting protein (PIP)-box, an eight-amino acid consensus sequence; different binding partners display a wide range of affinities based on function. Of all biological PIP-boxes, p21 has the highest known affinity for PCNA, allowing for inhibition of DNA replication and cell growth under cellular stress. As p21 is one of the few PIP-box sequences to contain a tyrosine rather than a phenylalanine in the eighth conserved position, we probed the significance of the hydroxyl group at this position using a mutational approach. Here we present the cocrystal structure of PCNA bound to a mutant p21 PIP-box peptide, p21Tyr151Phe, with associated isothermal titration calorimetry data. The p21Tyr151Phe peptide showed a 3-fold difference in affinity, as well as differences in entropy and enthalpy of binding. These differences can be attributed to a loss of hydrogen bonding capacity, as well as structural plasticity in the PCNA interdomain connector loop and the hydrophobic cavity of PCNA to which p21 binds. Thus, the hydroxyl group of Tyr151 in p21 acts as a tethering point for ideal packing and surface recognition of the peptide interface, increasing the binding affinity of p21 for PCNA.
p21 Exploits Residue Tyr151 as a Tether for High-Affinity PCNA Binding.,Kroker AJ, Bruning JB Biochemistry. 2015 Jun 9;54(22):3483-93. doi: 10.1021/acs.biochem.5b00241. Epub, 2015 May 27. PMID:25972089[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805-16. PMID:8242751
- ↑ LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997 Apr 1;11(7):847-62. PMID:9106657
- ↑ Kroker AJ, Bruning JB. p21 Exploits Residue Tyr151 as a Tether for High-Affinity PCNA Binding. Biochemistry. 2015 Jun 9;54(22):3483-93. doi: 10.1021/acs.biochem.5b00241. Epub, 2015 May 27. PMID:25972089 doi:http://dx.doi.org/10.1021/acs.biochem.5b00241
|
