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[[Image:2gtx.gif|left|200px]]
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{{STRUCTURE_2gtx|  PDB=2gtx  |  SCENE=  }}
'''Structural Basis of Catalysis by Mononuclear Methionine Aminopeptidase'''


==Structural Basis of Catalysis by Mononuclear Methionine Aminopeptidase==
<StructureSection load='2gtx' size='340' side='right'caption='[[2gtx]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2gtx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GTX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GTX 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]] 2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NLP:(1-AMINO-PENTYL)-PHOSPHONIC+ACID'>NLP</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=2gtx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gtx OCA], [https://pdbe.org/2gtx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gtx RCSB], [https://www.ebi.ac.uk/pdbsum/2gtx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gtx ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MAP1_ECOLI MAP1_ECOLI] 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]<ref>PMID:20521764</ref> <ref>PMID:3027045</ref>
== 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/gt/2gtx_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=2gtx ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Methionine aminopeptidase (MetAP) removes the amino-terminal methionine residue from newly synthesized proteins, and it is a target for the development of antibacterial and anticancer agents. Available x-ray structures of MetAP, as well as other metalloaminopeptidases, show an active site containing two adjacent divalent metal ions bridged by a water molecule or hydroxide ion. The predominance of dimetalated structures leads naturally to proposed mechanisms of catalysis involving both metal ions. However, kinetic studies indicate that in many cases, only a single metal ion is required for full activity. By limiting the amount of metal ion present during crystal growth, we have now obtained a crystal structure for a complex of Escherichia coli MetAP with norleucine phosphonate, a transition-state analog, and only a single Mn(II) ion bound at the active site in the position designated M1, and three related structures of the same complex that show the transition from the mono-Mn(II) form to the di-Mn(II) form. An unliganded structure was also solved. In view of the full kinetic competence of the monometalated MetAP, the much weaker binding constant for occupancy of the M2 site compared with the M1 site, and the newly determined structures, we propose a revised mechanism of peptide bond hydrolysis by E. coli MetAP. We also suggest that the crystallization of dimetalated forms of metallohydrolases may, in some cases, be a misleading experimental artifact, and caution must be taken when structures are generated to aid in elucidation of reaction mechanisms or to support structure-aided drug design efforts.


==Overview==
Structural basis of catalysis by monometalated methionine aminopeptidase.,Ye QZ, Xie SX, Ma ZQ, Huang M, Hanzlik RP Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9470-5. Epub 2006 Jun 12. PMID:16769889<ref>PMID:16769889</ref>
Methionine aminopeptidase (MetAP) removes the amino-terminal methionine residue from newly synthesized proteins, and it is a target for the development of antibacterial and anticancer agents. Available x-ray structures of MetAP, as well as other metalloaminopeptidases, show an active site containing two adjacent divalent metal ions bridged by a water molecule or hydroxide ion. The predominance of dimetalated structures leads naturally to proposed mechanisms of catalysis involving both metal ions. However, kinetic studies indicate that in many cases, only a single metal ion is required for full activity. By limiting the amount of metal ion present during crystal growth, we have now obtained a crystal structure for a complex of Escherichia coli MetAP with norleucine phosphonate, a transition-state analog, and only a single Mn(II) ion bound at the active site in the position designated M1, and three related structures of the same complex that show the transition from the mono-Mn(II) form to the di-Mn(II) form. An unliganded structure was also solved. In view of the full kinetic competence of the monometalated MetAP, the much weaker binding constant for occupancy of the M2 site compared with the M1 site, and the newly determined structures, we propose a revised mechanism of peptide bond hydrolysis by E. coli MetAP. We also suggest that the crystallization of dimetalated forms of metallohydrolases may, in some cases, be a misleading experimental artifact, and caution must be taken when structures are generated to aid in elucidation of reaction mechanisms or to support structure-aided drug design efforts.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2GTX is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GTX OCA].
</div>
<div class="pdbe-citations 2gtx" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Structural basis of catalysis by monometalated methionine aminopeptidase., Ye QZ, Xie SX, Ma ZQ, Huang M, Hanzlik RP, Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9470-5. Epub 2006 Jun 12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16769889 16769889]
*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
[[Category: Methionyl aminopeptidase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Ye QZ]]
[[Category: Ye, Q Z]]
[[Category: Enzyme-inhibitor complex]]
[[Category: Hydrolase]]
[[Category: Metalloenzyme]]
[[Category: Mononuclear]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 05:31:57 2008''

Latest revision as of 12:47, 30 August 2023

Structural Basis of Catalysis by Mononuclear Methionine AminopeptidaseStructural Basis of Catalysis by Mononuclear Methionine Aminopeptidase

Structural highlights

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

Function

MAP1_ECOLI 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][1] [2]

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) removes the amino-terminal methionine residue from newly synthesized proteins, and it is a target for the development of antibacterial and anticancer agents. Available x-ray structures of MetAP, as well as other metalloaminopeptidases, show an active site containing two adjacent divalent metal ions bridged by a water molecule or hydroxide ion. The predominance of dimetalated structures leads naturally to proposed mechanisms of catalysis involving both metal ions. However, kinetic studies indicate that in many cases, only a single metal ion is required for full activity. By limiting the amount of metal ion present during crystal growth, we have now obtained a crystal structure for a complex of Escherichia coli MetAP with norleucine phosphonate, a transition-state analog, and only a single Mn(II) ion bound at the active site in the position designated M1, and three related structures of the same complex that show the transition from the mono-Mn(II) form to the di-Mn(II) form. An unliganded structure was also solved. In view of the full kinetic competence of the monometalated MetAP, the much weaker binding constant for occupancy of the M2 site compared with the M1 site, and the newly determined structures, we propose a revised mechanism of peptide bond hydrolysis by E. coli MetAP. We also suggest that the crystallization of dimetalated forms of metallohydrolases may, in some cases, be a misleading experimental artifact, and caution must be taken when structures are generated to aid in elucidation of reaction mechanisms or to support structure-aided drug design efforts.

Structural basis of catalysis by monometalated methionine aminopeptidase.,Ye QZ, Xie SX, Ma ZQ, Huang M, Hanzlik RP Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9470-5. Epub 2006 Jun 12. PMID:16769889[3]

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

See Also

References

  1. ↑ Xiao Q, Zhang F, Nacev BA, Liu JO, Pei D. Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry. 2010 Jul 6;49(26):5588-99. doi: 10.1021/bi1005464. PMID:20521764 doi:http://dx.doi.org/10.1021/bi1005464
  2. ↑ Ben-Bassat A, Bauer K, Chang SY, Myambo K, Boosman A, Chang S. Processing of the initiation methionine from proteins: properties of the Escherichia coli methionine aminopeptidase and its gene structure. J Bacteriol. 1987 Feb;169(2):751-7. PMID:3027045
  3. ↑ Ye QZ, Xie SX, Ma ZQ, Huang M, Hanzlik RP. Structural basis of catalysis by monometalated methionine aminopeptidase. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9470-5. Epub 2006 Jun 12. PMID:16769889

2gtx, resolution 2.00Å

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