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| | ==Crystal structure of methionine aminopeptidase from Rickettsia prowazekii== | | ==Crystal structure of methionine aminopeptidase from Rickettsia prowazekii== |
| - | <StructureSection load='3mr1' size='340' side='right' caption='[[3mr1]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='3mr1' size='340' side='right'caption='[[3mr1]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3mr1]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_vr-142 Atcc vr-142]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MR1 FirstGlance]. <br> | + | <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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3mx6|3mx6]]</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">map, Q9ZCD3, RP824 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=782 ATCC VR-142])</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> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Methionyl_aminopeptidase Methionyl aminopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.11.18 3.4.11.18] </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=3mr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mr1 OCA], [http://pdbe.org/3mr1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mr1 RCSB], [http://www.ebi.ac.uk/pdbsum/3mr1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mr1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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] | + | [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 == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Aminopeptidase|Aminopeptidase]] | + | *[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Atcc vr-142]] | + | [[Category: Large Structures]] |
| - | [[Category: Methionyl aminopeptidase]] | + | [[Category: Rickettsia prowazekii]] |
| - | [[Category: Structural genomic]]
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| - | [[Category: Aminopeptidase]]
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| - | [[Category: Epidemic typhus]]
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| - | [[Category: Hydrolase]]
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| - | [[Category: Lice-born pathogen]]
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| - | [[Category: Metalloenzyme]]
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| - | [[Category: Niaid]]
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| - | [[Category: Protease]]
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| - | [[Category: Ssgcid]]
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| Structural highlights
Function
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
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Helgren TR, Chen C, Wangtrakuldee P, Edwards TE, Staker BL, Abendroth J, Sankaran B, Housley NA, Myler PJ, Audia JP, Horn JR, Hagen TJ. Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents. Bioorg Med Chem. 2017 Feb 1;25(3):813-824. doi: 10.1016/j.bmc.2016.11.013. Epub, 2016 Nov 10. PMID:28089350 doi:http://dx.doi.org/10.1016/j.bmc.2016.11.013
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