3mr1: Difference between revisions
New page: '''Unreleased structure''' The entry 3mr1 is ON HOLD Authors: Seattle Structural Genomics Center for Infectious Disease (SSGCID) Description: Crystal structure of methionine aminopepti... |
No edit summary |
||
| (9 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal structure of methionine aminopeptidase from Rickettsia prowazekii== | ||
<StructureSection load='3mr1' size='340' side='right'caption='[[3mr1]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mr1]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rickettsia_prowazekii Rickettsia prowazekii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MR1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MR1 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=3mr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mr1 OCA], [https://pdbe.org/3mr1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mr1 RCSB], [https://www.ebi.ac.uk/pdbsum/3mr1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mr1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MAP1_RICPR MAP1_RICPR] Removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Requires deformylation of the N(alpha)-formylated initiator methionine before it can be hydrolyzed.[HAMAP-Rule:MF_01974] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mr/3mr1_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</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=3mr1 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. We tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock was then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. These data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection. | |||
Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents.,Helgren TR, Chen C, Wangtrakuldee P, Edwards TE, Staker BL, Abendroth J, Sankaran B, Housley NA, Myler PJ, Audia JP, Horn JR, Hagen TJ Bioorg Med Chem. 2017 Feb 1;25(3):813-824. doi: 10.1016/j.bmc.2016.11.013. Epub, 2016 Nov 10. PMID:28089350<ref>PMID:28089350</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3mr1" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Rickettsia prowazekii]] | |||
Latest revision as of 11:59, 6 September 2023
Crystal structure of methionine aminopeptidase from Rickettsia prowazekiiCrystal structure of methionine aminopeptidase from Rickettsia prowazekii
Structural highlights
FunctionMAP1_RICPR Removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Requires deformylation of the N(alpha)-formylated initiator methionine before it can be hydrolyzed.[HAMAP-Rule:MF_01974] 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 PubMedMethionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. We tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock was then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. These data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection. Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents.,Helgren TR, Chen C, Wangtrakuldee P, Edwards TE, Staker BL, Abendroth J, Sankaran B, Housley NA, Myler PJ, Audia JP, Horn JR, Hagen TJ Bioorg Med Chem. 2017 Feb 1;25(3):813-824. doi: 10.1016/j.bmc.2016.11.013. Epub, 2016 Nov 10. PMID:28089350[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||