2zlf

From Proteopedia

(Difference between revisions)

Current revision

The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase

Structural highlights

2zlf is a 2 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.59Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RIR1_YEAST Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Eukaryotic ribonucleotide reductase (RR) catalyzes nucleoside diphosphate conversion to deoxynucleoside diphosphate. Crucial for rapidly dividing cells, RR is a target for cancer therapy. RR activity requires formation of a complex between subunits R1 and R2 in which the R2 C-terminal peptide binds to R1. Here we report crystal structures of heterocomplexes containing mammalian R2 C-terminal heptapeptide, P7 (Ac-1FTLDADF7) and its peptidomimetic P6 (1Fmoc(Me)PhgLDChaDF7) bound to Saccharomyces cerevisiae R1 (ScR1). P7 and P6, both of which inhibit ScRR, each bind at two contiguous sites containing residues that are highly conserved among eukaryotes. Such binding is quite distinct from that reported for prokaryotes. The Fmoc group in P6 peptide makes several hydrophobic interactions that contribute to its enhanced potency in binding to ScR1. Combining all of our results, we observe three distinct conformations for peptide binding to ScR1. These structures provide pharmacophores for designing highly potent nonpeptide class I RR inhibitors.

The structural basis for peptidomimetic inhibition of eukaryotic ribonucleotide reductase: a conformationally flexible pharmacophore.,Xu H, Fairman JW, Wijerathna SR, Kreischer NR, LaMacchia J, Helmbrecht E, Cooperman BS, Dealwis C J Med Chem. 2008 Aug 14;51(15):4653-9. Epub 2008 Jul 9. PMID:18610997^[2]

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

References

↑ Domkin V, Thelander L, Chabes A. Yeast DNA damage-inducible Rnr3 has a very low catalytic activity strongly stimulated after the formation of a cross-talking Rnr1/Rnr3 complex. J Biol Chem. 2002 May 24;277(21):18574-8. Epub 2002 Mar 13. PMID:11893751 doi:http://dx.doi.org/10.1074/jbc.M201553200
↑ Xu H, Fairman JW, Wijerathna SR, Kreischer NR, LaMacchia J, Helmbrecht E, Cooperman BS, Dealwis C. The structural basis for peptidomimetic inhibition of eukaryotic ribonucleotide reductase: a conformationally flexible pharmacophore. J Med Chem. 2008 Aug 14;51(15):4653-9. Epub 2008 Jul 9. PMID:18610997 doi:10.1021/jm800350u

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2zlf"

@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:2zlf.png|left|200px]]
-<!--
+==The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase==
-The line below this paragraph, containing "STRUCTURE_2zlf", creates the "Structure Box" on the page.
+<StructureSection load='2zlf' size='340' side='right'caption='[[2zlf]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2zlf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZLF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZLF FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.59&#8491;</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=2zlf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zlf OCA], [https://pdbe.org/2zlf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2zlf RCSB], [https://www.ebi.ac.uk/pdbsum/2zlf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2zlf ProSAT]</span></td></tr>
-{{STRUCTURE_2zlf|  PDB=2zlf  |  SCENE=  }}
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/RIR1_YEAST RIR1_YEAST] Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.<ref>PMID:11893751</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zl/2zlf_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2zlf ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Eukaryotic ribonucleotide reductase (RR) catalyzes nucleoside diphosphate conversion to deoxynucleoside diphosphate. Crucial for rapidly dividing cells, RR is a target for cancer therapy. RR activity requires formation of a complex between subunits R1 and R2 in which the R2 C-terminal peptide binds to R1. Here we report crystal structures of heterocomplexes containing mammalian R2 C-terminal heptapeptide, P7 (Ac-1FTLDADF7) and its peptidomimetic P6 (1Fmoc(Me)PhgLDChaDF7) bound to Saccharomyces cerevisiae R1 (ScR1). P7 and P6, both of which inhibit ScRR, each bind at two contiguous sites containing residues that are highly conserved among eukaryotes. Such binding is quite distinct from that reported for prokaryotes. The Fmoc group in P6 peptide makes several hydrophobic interactions that contribute to its enhanced potency in binding to ScR1. Combining all of our results, we observe three distinct conformations for peptide binding to ScR1. These structures provide pharmacophores for designing highly potent nonpeptide class I RR inhibitors.
-===The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase===
+The structural basis for peptidomimetic inhibition of eukaryotic ribonucleotide reductase: a conformationally flexible pharmacophore.,Xu H, Fairman JW, Wijerathna SR, Kreischer NR, LaMacchia J, Helmbrecht E, Cooperman BS, Dealwis C J Med Chem. 2008 Aug 14;51(15):4653-9. Epub 2008 Jul 9. PMID:18610997<ref>PMID:18610997</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2zlf" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_18610997}}, adds the Publication Abstract to the page
+*[[Ribonucleotide reductase 3D structures|Ribonucleotide reductase 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 18610997 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_18610997}}
+__TOC__
+</StructureSection>
-==About this Structure==
+[[Category: Large Structures]]
-ZLF is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZLF OCA].
-==Reference==
-<ref group="xtra">PMID:18610997</ref><references group="xtra"/>
-[[Category: Ribonucleoside-diphosphate reductase]]
 [[Category: Saccharomyces cerevisiae]]
-[[Category: Cooperman, B S.]]
+[[Category: Cooperman BS]]
-[[Category: Dealwis, C.]]
+[[Category: Dealwis C]]
-[[Category: Fairman, J W.]]
+[[Category: Fairman JW]]
-[[Category: Helmbrecht, E.]]
+[[Category: Helmbrecht E]]
-[[Category: Kreischer, N R.]]
+[[Category: Kreischer NR]]
-[[Category: LaMacchia, J.]]
+[[Category: LaMacchia J]]
-[[Category: Wijerathna, S R.]]
+[[Category: Wijerathna SR]]
-[[Category: Xu, H.]]
+[[Category: Xu H]]
-[[Category: Allosteric enzyme]]
-[[Category: Atp-binding]]
-[[Category: Cytoplasm]]
-[[Category: Dna replication]]
-[[Category: Nucleotide-binding]]
-[[Category: Oxidoreductase]]
-[[Category: Peptidomimetic inhibition eukaryotic ribonucleotide reductase]]
-[[Category: Phosphoprotein]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 18 07:51:53 2009''

2zlf

From Proteopedia

Current revision

The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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