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==Crystal structure of a smt fusion peptidyl-prolyl cis-trans isomerase with surface mutation v3i from burkholderia pseudomallei complexed with fk506== | |||
<StructureSection load='3vaw' size='340' side='right' caption='[[3vaw]], [[Resolution|resolution]] 1.55Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3vaw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Burp1 Burp1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VAW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VAW FirstGlance]. <br> | |||
==Function== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FK5:8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN'>FK5</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3uqa|3uqa]], [[3uqb|3uqb]], [[3uf8|3uf8]], [[2l2s|2l2s]], [[2ko7|2ko7]], [[2keo|2keo]], [[4dz2|4dz2]], [[4dz3|4dz3]], [[4fn2|4fn2]], [[4g50|4g50]], [[4ggq|4ggq]], [[4giv|4giv]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMT3, BURPS1710b_A0907 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=320372 BURP1])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></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=3vaw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vaw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3vaw RCSB], [http://www.ebi.ac.uk/pdbsum/3vaw PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/SMT3_YEAST SMT3_YEAST]] Not known; suppressor of MIF2 mutations. | [[http://www.uniprot.org/uniprot/SMT3_YEAST SMT3_YEAST]] Not known; suppressor of MIF2 mutations. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery. | |||
A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins.,Begley DW, Fox D 3rd, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, Barnes SR, Moen SO, Raymond AC, Stacy R, Myler PJ, Staker BL, Harmer NJ, Norville IH, Holzgrabe U, Sarkar-Tyson M, Edwards TE, Lorimer DD Antimicrob Agents Chemother. 2014 Mar;58(3):1458-67. doi: 10.1128/AAC.01875-13., Epub 2013 Dec 23. PMID:24366729<ref>PMID:24366729</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Burp1]] | [[Category: Burp1]] | ||
[[Category: Peptidylprolyl isomerase]] | [[Category: Peptidylprolyl isomerase]] | ||
[[Category: | [[Category: Structural genomic]] | ||
[[Category: Isomerase]] | [[Category: Isomerase]] | ||
[[Category: Protein binding]] | [[Category: Protein binding]] | ||
[[Category: Protein binding-inhibitor complex]] | [[Category: Protein binding-inhibitor complex]] | ||
[[Category: Ssgcid]] | [[Category: Ssgcid]] | ||
Revision as of 02:28, 25 December 2014
Crystal structure of a smt fusion peptidyl-prolyl cis-trans isomerase with surface mutation v3i from burkholderia pseudomallei complexed with fk506Crystal structure of a smt fusion peptidyl-prolyl cis-trans isomerase with surface mutation v3i from burkholderia pseudomallei complexed with fk506
Structural highlights
Function[SMT3_YEAST] Not known; suppressor of MIF2 mutations. Publication Abstract from PubMedMacrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery. A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins.,Begley DW, Fox D 3rd, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, Barnes SR, Moen SO, Raymond AC, Stacy R, Myler PJ, Staker BL, Harmer NJ, Norville IH, Holzgrabe U, Sarkar-Tyson M, Edwards TE, Lorimer DD Antimicrob Agents Chemother. 2014 Mar;58(3):1458-67. doi: 10.1128/AAC.01875-13., Epub 2013 Dec 23. PMID:24366729[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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