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2vd4

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Revision as of 07:46, 25 June 2020

Structure of small-molecule inhibitor of Glmu from Haemophilus influenzae reveals an allosteric binding site

Structural highlights

2vd4 is a 1 chain structure with sequence from "bacterium_influenzae"_lehmann_and_neumann_1896 "bacterium influenzae" lehmann and neumann 1896. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	2v0i, 2v0l, 2v0h, 2v0j, 2v0k
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.

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

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2vd4"

@@ Line 1: / Line 1: @@
 ==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]] 1.90&Aring;' scene=''>
+<StructureSection load='2vd4' size='340' side='right'caption='[[2vd4]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == 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 [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://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='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='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='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'>[http://proteopedia.org/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>
 </table>
 == Function ==
@@ Line 29: / Line 29: @@
 </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/>
@@ Line 34: / Line 37: @@
 </StructureSection>
 [[Category: Bacterium influenzae lehmann and neumann 1896]]
+[[Category: Large Structures]]
 [[Category: Lightle, S]]
 [[Category: McDowell, L]]

2vd4

From Proteopedia

Revision as of 07:46, 25 June 2020

Structure of small-molecule inhibitor of Glmu from Haemophilus influenzae reveals an allosteric binding site

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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