2vd4

From Proteopedia

(Difference between revisions)

Current revision

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 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.

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"

Categories: Haemophilus influenzae | Large Structures | Lightle S | McDowell L | Mochalkin I

@@ Line 1: / Line 1: @@
-[[Image:2vd4.jpg|left|200px]]<br /><applet load="2vd4" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2vd4, resolution 1.90&Aring;" />
-'''STRUCTURE OF SMALL-MOLECULE INHIBITOR OF GLMU FROM HAEMOPHILUS INFLUENZAE REVEALS AN ALLOSTERIC BINDING SITE'''<br />
-==About this Structure==
+==Structure of small-molecule inhibitor of Glmu from Haemophilus influenzae reveals an allosteric binding site==
-VD4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Haemophilus_influenzae Haemophilus influenzae] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=P21:'>P21</scene>, <scene name='pdbligand=PG4:'>PG4</scene> and <scene name='pdbligand=PGE:'>PGE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <scene name='pdbsite=AC1:P21 Binding Site For Chain A'>AC1</scene>, <scene name='pdbsite=AC2:So4 Binding Site For Chain A'>AC2</scene>, <scene name='pdbsite=AC3:So4 Binding Site For Chain A'>AC3</scene>, <scene name='pdbsite=AC4:So4 Binding Site For Chain A'>AC4</scene>, <scene name='pdbsite=AC5:So4 Binding Site For Chain A'>AC5</scene>, <scene name='pdbsite=AC6:So4 Binding Site For Chain A'>AC6</scene>, <scene name='pdbsite=AC7:So4 Binding Site For Chain A'>AC7</scene>, <scene name='pdbsite=AC8:Pg4 Binding Site For Chain A'>AC8</scene>, <scene name='pdbsite=AC9:Pg4 Binding Site For Chain A'>AC9</scene>, <scene name='pdbsite=BC1:Pge Binding Site For Chain A'>BC1</scene>, <scene name='pdbsite=BC2:Mg Binding Site For Chain A'>BC2</scene> and <scene name='pdbsite=BC3:Mg Binding Site For Chain A'>BC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VD4 OCA].
+<StructureSection load='2vd4' size='340' side='right'caption='[[2vd4]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
-[[Category: Haemophilus influenzae]]
+== Structural highlights ==
-[[Category: Single protein]]
+<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>
-[[Category: Lightle, S.]]
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
-[[Category: Mcdowell, L.]]
+<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>
-[[Category: Mochalkin, I.]]
+<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>
-[[Category: MG]]
+</table>
-[[Category: P21]]
+== Function ==
-[[Category: PG4]]
+[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>
-[[Category: PGE]]
+== Evolutionary Conservation ==
-[[Category: SO4]]
+[[Image:Consurf_key_small.gif|200px|right]]
-[[Category: active site]]
+Check<jmol>
-[[Category: acyltransferase]]
+  <jmolCheckbox>
-[[Category: allosteric]]
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vd/2vd4_consurf.spt"</scriptWhenChecked>
-[[Category: cell shape]]
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
-[[Category: cell wall biogenesis/degradation]]
+    <text>to colour the structure by Evolutionary Conservation</text>
-[[Category: cytoplasm]]
+  </jmolCheckbox>
-[[Category: glmu]]
+</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=2vd4 ConSurf].
-[[Category: inhibitor]]
+<div style="clear:both"></div>
-[[Category: magnesium]]
+<div style="background-color:#fffaf0;">
-[[Category: metal-binding]]
+== Publication Abstract from PubMed ==
-[[Category: multifunctional enzyme]]
+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.
-[[Category: nucleotidyltransferase]]
-[[Category: peptidoglycan synthesis]]
-[[Category: transferase]]
-[[Category: uridyltransferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:10:09 2008''
+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<ref>PMID:18218712</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</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/>
+__TOC__
+</StructureSection>
+[[Category: Haemophilus influenzae]]
+[[Category: Large Structures]]
+[[Category: Lightle S]]
+[[Category: McDowell L]]
+[[Category: Mochalkin I]]

2vd4

From Proteopedia

Current revision

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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