4x3v: Difference between revisions
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==Crystal structure of human ribonucleotide reductase 1 bound to inhibitor== | ==Crystal structure of human ribonucleotide reductase 1 bound to inhibitor== | ||
<StructureSection load='4x3v' size='340' side='right' caption='[[4x3v]], [[Resolution|resolution]] 3.70Å' scene=''> | <StructureSection load='4x3v' size='340' side='right'caption='[[4x3v]], [[Resolution|resolution]] 3.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4x3v]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X3V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X3V FirstGlance]. <br> | <table><tr><td colspan='2'>[[4x3v]] is a 2 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=4X3V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X3V FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3X4:N~6~-{N-[(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ACETYL]-2-METHYL-D-ALANYL}-D-LYSINE'>3X4</scene>, <scene name='pdbligand=TTP:THYMIDINE-5-TRIPHOSPHATE'>TTP</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3X4:N~6~-{N-[(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ACETYL]-2-METHYL-D-ALANYL}-D-LYSINE'>3X4</scene>, <scene name='pdbligand=TTP:THYMIDINE-5-TRIPHOSPHATE'>TTP</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RRM1, RR1 ([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/Ribonucleoside-diphosphate_reductase Ribonucleoside-diphosphate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.17.4.1 1.17.4.1] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ribonucleoside-diphosphate_reductase Ribonucleoside-diphosphate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.17.4.1 1.17.4.1] </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=4x3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x3v OCA], [http://pdbe.org/4x3v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x3v RCSB], [http://www.ebi.ac.uk/pdbsum/4x3v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x3v 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=4x3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x3v OCA], [http://pdbe.org/4x3v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x3v RCSB], [http://www.ebi.ac.uk/pdbsum/4x3v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x3v ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 4x3v" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4x3v" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Ribonucleotide reductase|Ribonucleotide reductase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Ribonucleoside-diphosphate reductase]] | [[Category: Ribonucleoside-diphosphate reductase]] | ||
[[Category: Ahmad, M F]] | [[Category: Ahmad, M F]] | ||
Revision as of 11:42, 4 December 2019
Crystal structure of human ribonucleotide reductase 1 bound to inhibitorCrystal structure of human ribonucleotide reductase 1 bound to inhibitor
Structural highlights
Function[RIR1_HUMAN] Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Publication Abstract from PubMedRibonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme. Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators.,Ahmad MF, Huff SE, Pink J, Alam I, Zhang A, Perry K, Harris ME, Misko T, Porwal SK, Oleinick NL, Miyagi M, Viswanathan R, Dealwis CG J Med Chem. 2015 Dec 24;58(24):9498-509. doi: 10.1021/acs.jmedchem.5b00929. Epub , 2015 Dec 9. PMID:26488902[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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