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| | ==Crystal Structure of Nicotinate Mononucleotide Adenylyltransferase from Mycobacterium tuberculosis== | | ==Crystal Structure of Nicotinate Mononucleotide Adenylyltransferase from Mycobacterium tuberculosis== |
| - | <StructureSection load='4rpi' size='340' side='right' caption='[[4rpi]], [[Resolution|resolution]] 2.42Å' scene=''> | + | <StructureSection load='4rpi' size='340' side='right'caption='[[4rpi]], [[Resolution|resolution]] 2.42Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rpi]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RPI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RPI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rpi]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RPI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RPI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">nadD, HKBS1_2563 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=4rpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rpi OCA], [https://pdbe.org/4rpi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rpi RCSB], [https://www.ebi.ac.uk/pdbsum/4rpi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rpi ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nicotinate-nucleotide_adenylyltransferase Nicotinate-nucleotide adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.18 2.7.7.18] </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=4rpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rpi OCA], [http://pdbe.org/4rpi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rpi RCSB], [http://www.ebi.ac.uk/pdbsum/4rpi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rpi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/W6GSY1_MYCTX W6GSY1_MYCTX]] Catalyzes the reversible adenylation of nicotinate mononucleotide (NaMN) to nicotinic acid adenine dinucleotide (NaAD).[HAMAP-Rule:MF_00244] | + | [https://www.uniprot.org/uniprot/NADD_MYCTU NADD_MYCTU] Catalyzes the reversible adenylation of nicotinate mononucleotide (NaMN) to nicotinic acid adenine dinucleotide (NaAD). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Nicotinate-nucleotide adenylyltransferase]] | + | [[Category: Large Structures]] |
| - | [[Category: Aleshin, A E]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Kazanov, M]] | + | [[Category: Aleshin AE]] |
| - | [[Category: Locher, C]] | + | [[Category: Kazanov M]] |
| - | [[Category: Osterman, A]] | + | [[Category: Locher C]] |
| - | [[Category: Rodionova, I]] | + | [[Category: Osterman A]] |
| - | [[Category: Rubin, E]] | + | [[Category: Rodionova I]] |
| - | [[Category: Sergienko, E]] | + | [[Category: Rubin E]] |
| - | [[Category: Sorci, L]] | + | [[Category: Sergienko E]] |
| - | [[Category: Zuccola, H]] | + | [[Category: Sorci L]] |
| - | [[Category: Nad biosynthesis]]
| + | [[Category: Zuccola H]] |
| - | [[Category: Nadd]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
NADD_MYCTU Catalyzes the reversible adenylation of nicotinate mononucleotide (NaMN) to nicotinic acid adenine dinucleotide (NaAD).
Publication Abstract from PubMed
Nicotinate mononucleotide adenylyltransferase NadD is an essential enzyme in the biosynthesis of the NAD cofactor, which has been implicated as a target for developing new antimycobacterial therapies. Here we report the crystal structure of Mycobacterium tuberculosis NadD (MtNadD) at a resolution of 2.4 A. A remarkable new feature of the MtNadD structure, compared with other members of this enzyme family, is a 310 helix that locks the active site in an over-closed conformation. As a result, MtNadD is rendered inactive as it is topologically incompatible with substrate binding and catalysis. Directed mutagenesis was also used to further dissect the structural elements that contribute to the interactions of the two MtNadD substrates, i.e. ATP and nicotinic acid mononucleotide (NaMN). For inhibitory profiling of partially active mutants and wild type MtNadD, we used a small molecule inhibitor of MtNadD with moderate affinity (Ki approximately 25 muM) and antimycobacterial activity (MIC80) approximately 40-80 muM). This analysis revealed interferences with some of the residues in the NaMN binding subsite consistent with the competitive inhibition observed for the NaMN substrate (but not ATP). A detailed steady-state kinetic analysis of MtNadD suggests that ATP must first bind to allow efficient NaMN binding and catalysis. This sequential mechanism is consistent with the requirement of transition to catalytically competent (open) conformation hypothesized from structural modeling. A possible physiological significance of this mechanism is to enable the down-regulation of NAD synthesis under ATP-limiting dormancy conditions. These findings point to a possible new strategy for designing inhibitors that lock the enzyme in the inactive over-closed conformation.
Mycobacterial nicotinate mononucleotide adenylyltransferase: structure, mechanism, and implications for drug discovery.,Rodionova IA, Zuccola HJ, Sorci L, Aleshin AE, Kazanov MD, Ma CT, Sergienko E, Rubin EJ, Locher CP, Osterman AL J Biol Chem. 2015 Mar 20;290(12):7693-706. doi: 10.1074/jbc.M114.628016. Epub, 2015 Jan 28. PMID:25631047[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Rodionova IA, Zuccola HJ, Sorci L, Aleshin AE, Kazanov MD, Ma CT, Sergienko E, Rubin EJ, Locher CP, Osterman AL. Mycobacterial nicotinate mononucleotide adenylyltransferase: structure, mechanism, and implications for drug discovery. J Biol Chem. 2015 Mar 20;290(12):7693-706. doi: 10.1074/jbc.M114.628016. Epub, 2015 Jan 28. PMID:25631047 doi:http://dx.doi.org/10.1074/jbc.M114.628016
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