7n8e

From Proteopedia

(Difference between revisions)

Current revision

PptT PAP(CoA) 9056 complex

Structural highlights

7n8e is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.74Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PPTT_MYCTU Transfers the 4'-phosphopantetheine moiety from coenzyme A to a Ser of acyl-carrier-protein (PubMed:9831524, PubMed:16709676, PubMed:25785780, PubMed:28203522). Involved in post-translational modification of various type-I polyketide synthases required for the formation of both mycolic acids and lipid virulence factors (PubMed:16709676). Acts on Pks13, Mas, PpsA, PpsB, PpsC and PpsD (PubMed:16709676, PubMed:28203522). Also acts on AcpM, the meromycolate extension acyl carrier protein (PubMed:25785780). In addition, is involved in the activation of the acyl carrier protein MbtL and the nonribosomal peptides synthases MbtB and MbtE, which are involved in the biosynthesis of the siderophore mycobactin (PubMed:9831524, PubMed:28203522).^[1] ^[2] ^[3] ^[4] Required for the replication and survival of Mycobacterium during the acute and chronic phases of infection in mice.^[5]

Publication Abstract from PubMed

A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Cav1.2 and Nav1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide).

In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas.,Ottavi S, Scarry SM, Mosior J, Ling Y, Roberts J, Singh A, Zhang D, Goullieux L, Roubert C, Bacque E, Lagiakos HR, Vendome J, Moraca F, Li K, Perkowski AJ, Ramesh R, Bowler MM, Tracy W, Feher VA, Sacchettini JC, Gold BS, Nathan CF, Aube J J Med Chem. 2022 Jan 19. doi: 10.1021/acs.jmedchem.1c01565. PMID:35044775^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chalut C, Botella L, de Sousa-D'Auria C, Houssin C, Guilhot C. The nonredundant roles of two 4'-phosphopantetheinyl transferases in vital processes of Mycobacteria. Proc Natl Acad Sci U S A. 2006 May 30;103(22):8511-6. doi:, 10.1073/pnas.0511129103. Epub 2006 May 18. PMID:16709676 doi:http://dx.doi.org/10.1073/pnas.0511129103
↑ Zimhony O, Schwarz A, Raitses-Gurevich M, Peleg Y, Dym O, Albeck S, Burstein Y, Shakked Z. AcpM, the meromycolate extension acyl carrier protein of Mycobacterium tuberculosis, is activated by the 4'-phosphopantetheinyl transferase PptT, a potential target of the multistep mycolic acid biosynthesis. Biochemistry. 2015 Apr 14;54(14):2360-71. doi: 10.1021/bi501444e. Epub 2015 Apr, 1. PMID:25785780 doi:http://dx.doi.org/10.1021/bi501444e
↑ Jung J, Bashiri G, Johnston JM, Baker EN. Mass spectral determination of phosphopantetheinylation specificity for carrier proteins in Mycobacterium tuberculosis. FEBS Open Bio. 2016 Oct 24;6(12):1220-1226. doi: 10.1002/2211-5463.12140., eCollection 2016 Dec. PMID:28203522 doi:http://dx.doi.org/10.1002/2211-5463.12140
↑ Quadri LE, Sello J, Keating TA, Weinreb PH, Walsh CT. Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem Biol. 1998 Nov;5(11):631-45. doi: 10.1016/s1074-5521(98)90291-5. PMID:9831524 doi:http://dx.doi.org/10.1016/s1074-5521(98)90291-5
↑ Leblanc C, Prudhomme T, Tabouret G, Ray A, Burbaud S, Cabantous S, Mourey L, Guilhot C, Chalut C. 4'-Phosphopantetheinyl transferase PptT, a new drug target required for Mycobacterium tuberculosis growth and persistence in vivo. PLoS Pathog. 2012 Dec;8(12):e1003097. doi: 10.1371/journal.ppat.1003097. Epub, 2012 Dec 20. PMID:23308068 doi:http://dx.doi.org/10.1371/journal.ppat.1003097
↑ Ottavi S, Scarry SM, Mosior J, Ling Y, Roberts J, Singh A, Zhang D, Goullieux L, Roubert C, Bacque E, Lagiakos HR, Vendome J, Moraca F, Li K, Perkowski AJ, Ramesh R, Bowler MM, Tracy W, Feher VA, Sacchettini JC, Gold BS, Nathan CF, Aube J. In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas. J Med Chem. 2022 Jan 19. doi: 10.1021/acs.jmedchem.1c01565. PMID:35044775 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01565

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7n8e"

Categories: Large Structures | Mycobacterium tuberculosis H37Rv | Mosior JW | Sacchettini JC

@@ Line 3: / Line 3: @@
 <StructureSection load='7n8e' size='340' side='right'caption='[[7n8e]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7n8e]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N8E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7n8e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N8E FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0UD:N-[2,6-di(propan-2-yl)phenyl]-N-(N-ethylcarbamimidoyl)urea'>0UD</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.74&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Holo-[acyl-carrier-protein]_synthase Holo-[acyl-carrier-protein] synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.8.7 2.7.8.7] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0UD:N-[2,6-di(propan-2-yl)phenyl]-N-(N-ethylcarbamimidoyl)urea'>0UD</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=7n8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n8e OCA], [https://pdbe.org/7n8e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n8e RCSB], [https://www.ebi.ac.uk/pdbsum/7n8e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n8e ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/PPTT_MYCTU PPTT_MYCTU]] Transfers the 4'-phosphopantetheine moiety from coenzyme A to a Ser of acyl-carrier-protein (PubMed:9831524, PubMed:16709676, PubMed:25785780, PubMed:28203522). Involved in post-translational modification of various type-I polyketide synthases required for the formation of both mycolic acids and lipid virulence factors (PubMed:16709676). Acts on Pks13, Mas, PpsA, PpsB, PpsC and PpsD (PubMed:16709676, PubMed:28203522). Also acts on AcpM, the meromycolate extension acyl carrier protein (PubMed:25785780). In addition, is involved in the activation of the acyl carrier protein MbtL and the nonribosomal peptides synthases MbtB and MbtE, which are involved in the biosynthesis of the siderophore mycobactin (PubMed:9831524, PubMed:28203522).<ref>PMID:16709676</ref> <ref>PMID:25785780</ref> <ref>PMID:28203522</ref> <ref>PMID:9831524</ref>   Required for the replication and survival of Mycobacterium during the acute and chronic phases of infection in mice.<ref>PMID:23308068</ref>
+[https://www.uniprot.org/uniprot/PPTT_MYCTU PPTT_MYCTU] Transfers the 4'-phosphopantetheine moiety from coenzyme A to a Ser of acyl-carrier-protein (PubMed:9831524, PubMed:16709676, PubMed:25785780, PubMed:28203522). Involved in post-translational modification of various type-I polyketide synthases required for the formation of both mycolic acids and lipid virulence factors (PubMed:16709676). Acts on Pks13, Mas, PpsA, PpsB, PpsC and PpsD (PubMed:16709676, PubMed:28203522). Also acts on AcpM, the meromycolate extension acyl carrier protein (PubMed:25785780). In addition, is involved in the activation of the acyl carrier protein MbtL and the nonribosomal peptides synthases MbtB and MbtE, which are involved in the biosynthesis of the siderophore mycobactin (PubMed:9831524, PubMed:28203522).<ref>PMID:16709676</ref> <ref>PMID:25785780</ref> <ref>PMID:28203522</ref> <ref>PMID:9831524</ref>   Required for the replication and survival of Mycobacterium during the acute and chronic phases of infection in mice.<ref>PMID:23308068</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Mosior, J W]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Sacchettini, J C]]
+[[Category: Mosior JW]]
-[[Category: Structural genomic]]
+[[Category: Sacchettini JC]]
-[[Category: Inhibitor]]
-[[Category: PSI, Protein structure initiative]]
-[[Category: Tbsgc]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]

7n8e

From Proteopedia

Current revision

PptT PAP(CoA) 9056 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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