|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Structure of small-molecule inhibitor of Glmu from Haemophilus influenzae reveals an allosteric binding site== | | ==Structure of small-molecule inhibitor of Glmu from Haemophilus influenzae reveals an allosteric binding site== |
| - | <StructureSection load='2vd4' size='340' side='right' caption='[[2vd4]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='2vd4' size='340' side='right'caption='[[2vd4]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vd4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacterium_influenzae"_lehmann_and_neumann_1896 "bacterium influenzae" lehmann and neumann 1896]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VD4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VD4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vd4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Haemophilus_influenzae Haemophilus influenzae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VD4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=P21:4-CHLORO-N-(3-METHOXYPROPYL)-N-[(3S)-1-(2-PHENYLETHYL)PIPERIDIN-3-YL]BENZAMIDE'>P21</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2v0i|2v0i]], [[2v0l|2v0l]], [[2v0h|2v0h]], [[2v0j|2v0j]], [[2v0k|2v0k]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=P21:4-CHLORO-N-(3-METHOXYPROPYL)-N-[(3S)-1-(2-PHENYLETHYL)PIPERIDIN-3-YL]BENZAMIDE'>P21</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vd4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vd4 OCA], [http://pdbe.org/2vd4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vd4 RCSB], [http://www.ebi.ac.uk/pdbsum/2vd4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2vd4 ProSAT]</span></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=2vd4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vd4 OCA], [https://pdbe.org/2vd4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vd4 RCSB], [https://www.ebi.ac.uk/pdbsum/2vd4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vd4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GLMU_HAEIN GLMU_HAEIN]] Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.<ref>PMID:18029420</ref> | + | [https://www.uniprot.org/uniprot/GLMU_HAEIN GLMU_HAEIN] Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.<ref>PMID:18029420</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 29: |
Line 29: |
| | </div> | | </div> |
| | <div class="pdbe-citations 2vd4" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 2vd4" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[N-acetylglucosamine-1-phosphate uridyltransferase|N-acetylglucosamine-1-phosphate uridyltransferase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacterium influenzae lehmann and neumann 1896]] | + | [[Category: Haemophilus influenzae]] |
| - | [[Category: Lightle, S]] | + | [[Category: Large Structures]] |
| - | [[Category: McDowell, L]] | + | [[Category: Lightle S]] |
| - | [[Category: Mochalkin, I]] | + | [[Category: McDowell L]] |
| - | [[Category: Active site]] | + | [[Category: Mochalkin I]] |
| - | [[Category: Acyltransferase]]
| + | |
| - | [[Category: Allosteric]]
| + | |
| - | [[Category: Cell shape]]
| + | |
| - | [[Category: Cell wall biogenesis/degradation]]
| + | |
| - | [[Category: Glmu]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Magnesium]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Multifunctional enzyme]]
| + | |
| - | [[Category: Nucleotidyltransferase]]
| + | |
| - | [[Category: Peptidoglycan synthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Uridyltransferase]]
| + | |
| Structural highlights
2vd4 is a 1 chain structure with sequence from Haemophilus influenzae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.9Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GLMU_HAEIN Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.[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
N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is an essential enzyme in aminosugars metabolism and an attractive target for antibiotic drug discovery. GlmU catalyzes the formation of uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), an important precursor in the peptidoglycan and lipopolisaccharide biosynthesis in both Gram-negative and Gram-positive bacteria. Here we disclose a 1.9 A resolution crystal structure of a synthetic small-molecule inhibitor of GlmU from Haemophilus influenzae (hiGlmU). The compound was identified through a high-throughput screening (HTS) configured to detect inhibitors that target the uridyltransferase active site of hiGlmU. The original HTS hit exhibited a modest micromolar potency (IC(50) approximately 18 microM in a racemic mixture) against hiGlmU and no activity against Staphylococcus aureus GlmU (saGlmU). The determined crystal structure indicated that the inhibitor occupies an allosteric site adjacent to the GlcNAc-1-P substrate-binding region. Analysis of the mechanistic model of the uridyltransferase reaction suggests that the binding of this allosteric inhibitor prevents structural rearrangements that are required for the enzymatic reaction, thus providing a basis for structure-guided design of a new class of mechanism-based inhibitors of GlmU.
Structure of a small-molecule inhibitor complexed with GlmU from Haemophilus influenzae reveals an allosteric binding site.,Mochalkin I, Lightle S, Narasimhan L, Bornemeier D, Melnick M, Vanderroest S, McDowell L Protein Sci. 2008 Mar;17(3):577-82. Epub 2008 Jan 24. PMID:18218712[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mochalkin I, Lightle S, Zhu Y, Ohren JF, Spessard C, Chirgadze NY, Banotai C, Melnick M, McDowell L. Characterization of substrate binding and catalysis in the potential antibacterial target N-acetylglucosamine-1-phosphate uridyltransferase (GlmU). Protein Sci. 2007 Dec;16(12):2657-66. PMID:18029420 doi:http://dx.doi.org/16/12/2657
- ↑ Mochalkin I, Lightle S, Narasimhan L, Bornemeier D, Melnick M, Vanderroest S, McDowell L. Structure of a small-molecule inhibitor complexed with GlmU from Haemophilus influenzae reveals an allosteric binding site. Protein Sci. 2008 Mar;17(3):577-82. Epub 2008 Jan 24. PMID:18218712 doi:10.1110/ps.073271408
|
