3qh4

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==Crystal structure of esterase LipW from Mycobacterium marinum==
==Crystal structure of esterase LipW from Mycobacterium marinum==
<StructureSection load='3qh4' size='340' side='right' caption='[[3qh4]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
<StructureSection load='3qh4' size='340' side='right' caption='[[3qh4]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3qh4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycmm Mycmm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QH4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QH4 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3qh4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QH4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QH4 FirstGlance]. <br>
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</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lipW, MMAR_0404 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=216594 MYCMM])</td></tr>
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</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=3qh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qh4 OCA], [http://pdbe.org/3qh4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qh4 RCSB], [http://www.ebi.ac.uk/pdbsum/3qh4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qh4 ProSAT]</span></td></tr>
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<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=3qh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qh4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qh4 RCSB], [http://www.ebi.ac.uk/pdbsum/3qh4 PDBsum]</span></td></tr>
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</table>
</table>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with &gt;55% overall sequence identity had active site Calpha RMSD &lt;1 A, &gt;85% side chain identity, and &gt;/=80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared &gt;55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.
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The complex life cycle of Mycobacterium tuberculosis requires diverse energy mobilization and utilization strategies facilitated by a battery of lipid metabolism enzymes. Among lipid metabolism enzymes, the Lip family of mycobacterial serine hydrolases is essential to lipid scavenging, metabolic cycles, and reactivation from dormancy. On the basis of the homologous rescue strategy for mycobacterial drug targets, we have characterized the three-dimensional structure of full length LipW from Mycobacterium marinum, the first structure of a catalytically active Lip family member. LipW contains a deep, expansive substrate-binding pocket with only a narrow, restrictive active site, suggesting tight substrate selectivity for short, unbranched esters. Structural alignment reinforced this strict substrate selectivity of LipW, as the binding pocket of LipW aligned most closely with the bacterial acyl esterase superfamily. Detailed kinetic analysis of two different LipW homologues confirmed this strict substrate selectivity, as each homologue selected for unbranched propionyl ester substrates, irrespective of the alcohol portion of the ester. Using comprehensive substitutional analysis across the binding pocket, the strict substrate selectivity of LipW for propionyl esters was assigned to a narrow funnel in the acyl-binding pocket capped by a key hydrophobic valine residue. The polar, negatively charged alcohol-binding pocket also contributed to substrate orientation and stabilization of rotameric states in the catalytic serine. Together, the structural, enzymatic, and substitutional analyses of LipW provide a connection between the structure and metabolic properties of a Lip family hydrolase that refines its biological function in active and dormant tuberculosis infection.
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Increasing the structural coverage of tuberculosis drug targets.,Baugh L, Phan I, Begley DW, Clifton MC, Armour B, Dranow DM, Taylor BM, Muruthi MM, Abendroth J, Fairman JW, Fox D 3rd, Dieterich SH, Staker BL, Gardberg AS, Choi R, Hewitt SN, Napuli AJ, Myers J, Barrett LK, Zhang Y, Ferrell M, Mundt E, Thompkins K, Tran N, Lyons-Abbott S, Abramov A, Sekar A, Serbzhinskiy D, Lorimer D, Buchko GW, Stacy R, Stewart LJ, Edwards TE, Van Voorhis WC, Myler PJ Tuberculosis (Edinb). 2014 Dec 19. pii: S1472-9792(14)20565-8. doi:, 10.1016/j.tube.2014.12.003. PMID:25613812<ref>PMID:25613812</ref>
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Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW.,McKary MG, Abendroth J, Edwards TE, Johnson RJ Biochemistry. 2016 Dec 12. PMID:27936614<ref>PMID:27936614</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
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<div class="pdbe-citations 3qh4" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Mycmm]]
 
[[Category: Structural genomic]]
[[Category: Structural genomic]]
[[Category: Esterase]]
[[Category: Esterase]]

Revision as of 14:56, 22 December 2016

Crystal structure of esterase LipW from Mycobacterium marinum

3qh4, resolution 1.75Å

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