1wma: Difference between revisions

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New page: left|200px<br /> <applet load="1wma" size="450" color="white" frame="true" align="right" spinBox="true" caption="1wma, resolution 1.24Å" /> '''Crystal structure o...
 
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[[Image:1wma.gif|left|200px]]<br />
<applet load="1wma" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1wma, resolution 1.24&Aring;" />
'''Crystal structure of human CBR1 in complex with Hydroxy-PP'''<br />


==Overview==
==Crystal structure of human CBR1 in complex with Hydroxy-PP==
We have implemented an unbiased cell morphology-based screen to identify, small-molecule modulators of cellular processes using the Cytometrix (TM), automated imaging and analysis system. This assay format provides unbiased, analysis of morphological effects induced by small molecules by capturing, phenotypic readouts of most known classes of pharmacological agents and, has the potential to read out pathways for which little is known. Four, human-cancer cell lines and one noncancerous primary cell type were, treated with 107 small molecules comprising four different protein, kinase-inhibitor scaffolds. Cellular phenotypes induced by each compound, were quantified by multivariate statistical analysis of the morphology, staining intensity, and spatial attributes of the cellular nuclei, microtubules, and Golgi compartments. Principal component analysis was, used to identify inhibitors of cellular components not targeted by known, protein kinase inhibitors. Here we focus on a hydroxyl-substituted analog, (hydroxy-PP) of the known Src-family kinase inhibitor PP2 because it, induced cell-specific morphological features distinct from all known, kinase inhibitors in the collection. We used affinity purification to, identify a target of hydroxy-PP, carbonyl reductase 1 (CBR1), a, short-chain dehydrogenase-reductase. We solved the X-ray crystal structure, of the CBR1/hydroxy-PP complex to 1.24 A resolution. Structure-based, design of more potent and selective CBR1 inhibitors provided probes for, analyzing the biological function of CBR1 in A549 cells. These studies, revealed a previously unknown function for CBR1 in, serum-withdrawal-induced apoptosis. Further studies indicate CBR1, inhibitors may enhance the effectiveness of anticancer anthracyclines., Morphology-based screening of diverse cancer cell types has provided a, method for discovering potent new small-molecule probes for cell, biological studies and anticancer drug candidates.
<StructureSection load='1wma' size='340' side='right'caption='[[1wma]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1wma]] is a 1 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=1WMA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1WMA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.24&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AB3:3-(4-AMINO-1-TERT-BUTYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-3-YL)PHENOL'>AB3</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene>, <scene name='pdbligand=PE5:3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL'>PE5</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=1wma FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wma OCA], [https://pdbe.org/1wma PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1wma RCSB], [https://www.ebi.ac.uk/pdbsum/1wma PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1wma ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CBR1_HUMAN CBR1_HUMAN] NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione.<ref>PMID:18449627</ref> <ref>PMID:15799708</ref> <ref>PMID:17912391</ref> <ref>PMID:18826943</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/wm/1wma_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=1wma ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
1WMA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4, AB3, NDP, PE5 and P33 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carbonyl_reductase_(NADPH) Carbonyl reductase (NADPH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.184 1.1.1.184] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1WMA OCA].
*[[Carbonyl reductase 3D structures|Carbonyl reductase 3D structures]]
 
== References ==
==Reference==
<references/>
An unbiased cell morphology-based screen for new, biologically active small molecules., Tanaka M, Bateman R, Rauh D, Vaisberg E, Ramachandani S, Zhang C, Hansen KC, Burlingame AL, Trautman JK, Shokat KM, Adams CL, PLoS Biol. 2005 May;3(5):e128. Epub 2005 Apr 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15799708 15799708]
__TOC__
[[Category: Carbonyl reductase (NADPH)]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Bateman, R.]]
[[Category: Bateman R]]
[[Category: Rauh, D.]]
[[Category: Rauh D]]
[[Category: Shokat, K.M.]]
[[Category: Shokat KM]]
[[Category: AB3]]
[[Category: NDP]]
[[Category: P33]]
[[Category: PE5]]
[[Category: SO4]]
[[Category: oxidoreductase]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:52:26 2007''

Latest revision as of 16:32, 13 March 2024

Crystal structure of human CBR1 in complex with Hydroxy-PPCrystal structure of human CBR1 in complex with Hydroxy-PP

Structural highlights

1wma is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.24Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CBR1_HUMAN NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione.[1] [2] [3] [4]

Evolutionary Conservation

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

See Also

References

  1. ↑ Gonzalez-Covarrubias V, Kalabus JL, Blanco JG. Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). Pharm Res. 2008 Jul;25(7):1730-4. doi: 10.1007/s11095-008-9592-5. Epub 2008 May, 1. PMID:18449627 doi:http://dx.doi.org/10.1007/s11095-008-9592-5
  2. ↑ Tanaka M, Bateman R, Rauh D, Vaisberg E, Ramachandani S, Zhang C, Hansen KC, Burlingame AL, Trautman JK, Shokat KM, Adams CL. An unbiased cell morphology-based screen for new, biologically active small molecules. PLoS Biol. 2005 May;3(5):e128. Epub 2005 Apr 5. PMID:15799708 doi:10.1371/journal.pbio.0030128
  3. ↑ Bateman R, Rauh D, Shokat KM. Glutathione traps formaldehyde by formation of a bicyclo[4.4.1]undecane adduct. Org Biomol Chem. 2007 Oct 21;5(20):3363-7. Epub 2007 Aug 29. PMID:17912391 doi:10.1039/b707602a
  4. ↑ Bateman RL, Rauh D, Tavshanjian B, Shokat KM. Human carbonyl reductase 1 is an S-nitrosoglutathione reductase. J Biol Chem. 2008 Dec 19;283(51):35756-62. Epub 2008 Sep 29. PMID:18826943 doi:10.1074/jbc.M807125200

1wma, resolution 1.24Å

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