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4l6c

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==Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor pib-t==
==Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor pib-t==
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<StructureSection load='4l6c' size='340' side='right' caption='[[4l6c]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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<StructureSection load='4l6c' size='340' side='right'caption='[[4l6c]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4l6c]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L6C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L6C FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4l6c]] 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=4L6C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L6C FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0BT:1-{2-DEOXY-3,5-O-[(4-IODOPHENYL)(PHOSPHONO)METHYLIDENE]-BETA-D-THREO-PENTOFURANOSYL}-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>0BT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4l6a|4l6a]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0BT:1-{2-DEOXY-3,5-O-[(4-IODOPHENYL)(PHOSPHONO)METHYLIDENE]-BETA-D-THREO-PENTOFURANOSYL}-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>0BT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<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=4l6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l6c OCA], [http://pdbe.org/4l6c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4l6c RCSB], [http://www.ebi.ac.uk/pdbsum/4l6c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4l6c ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4l6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l6c OCA], [https://pdbe.org/4l6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l6c RCSB], [https://www.ebi.ac.uk/pdbsum/4l6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l6c ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/NT5M_HUMAN NT5M_HUMAN]] Dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP. Has only marginal activity towards dIMP and dGMP.
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[https://www.uniprot.org/uniprot/NT5M_HUMAN NT5M_HUMAN] Dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP. Has only marginal activity towards dIMP and dGMP.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-beta-d-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K = 2.71 muM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 muM; iodoxy derivative, K = 6.60 muM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy.
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Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.,Simak O, Pachl P, Fabry M, Budesinsky M, Jandusik T, Hnizda A, Sklenickova R, Petrova M, Veverka V, Rezacova P, Brynda J, Rosenberg I Org Biomol Chem. 2014 Sep 1. PMID:25178098<ref>PMID:25178098</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4l6c" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Brynda, J]]
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[[Category: Homo sapiens]]
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[[Category: Pachl, P]]
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[[Category: Large Structures]]
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[[Category: Rezacova, P]]
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[[Category: Brynda J]]
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[[Category: 5'-nucleotidase]]
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[[Category: Pachl P]]
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[[Category: Dephosphorylation]]
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[[Category: Rezacova P]]
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[[Category: Had-like]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Mitochondria]]
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[[Category: Phosphorylation]]
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[[Category: Protein conformation]]
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[[Category: Sequence homology]]
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Current revision

Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor pib-t

PDB ID 4l6c

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