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[[Image:2tmn.jpg|left|200px]]
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{{STRUCTURE_2tmn|  PDB=2tmn  |  SCENE=  }}
'''CRYSTALLOGRAPHIC STRUCTURAL ANALYSIS OF PHOSPHORAMIDATES AS INHIBITORS AND TRANSITION-STATE ANALOGS OF THERMOLYSIN'''


==CRYSTALLOGRAPHIC STRUCTURAL ANALYSIS OF PHOSPHORAMIDATES AS INHIBITORS AND TRANSITION-STATE ANALOGS OF THERMOLYSIN==
<StructureSection load='2tmn' size='340' side='right'caption='[[2tmn]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2tmn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_thermoproteolyticus Bacillus thermoproteolyticus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2TMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2TMN 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]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0FA:N~2~-PHOSPHONO-L-LEUCINAMIDE'>0FA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2tmn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2tmn OCA], [https://pdbe.org/2tmn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2tmn RCSB], [https://www.ebi.ac.uk/pdbsum/2tmn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2tmn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/THER_BACTH THER_BACTH] Extracellular zinc metalloprotease.
== 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/tm/2tmn_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=2tmn ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The mode of binding to thermolysin of the unsubstituted phosphoramidate inhibitor N-phosphoryl-L-leucinamide (P-Leu-NH2) has been determined crystallographically and refined at high resolution (R = 17.9% to 0.16-nm resolution). The mode of binding of the naturally occurring thermolysin inhibitor phosphoramidon reported previously [Weaver, L. H., Kester, W. R. and Matthews, B. W. (1977) J. Mol. Biol. 114, 119-132] has also been confirmed by crystallographic refinement (R = 17.4% to 0.23-nm resolution). Phosphoramidon binds to the enzyme with a single oxygen of the phosphoramidate moiety as a zinc ligand. Together with three ligands to the metal from the protein the resultant complex has approximately tetrahedral geometry. However, in the case of P-Leu-NH2, two of the phosphoramidate oxygens interact with the zinc to form a complex that tends towards pentacoordinate. In this respect, P-Leu-NH2 appears to be a better transition-state analog than is phosphoramidon. In addition, the phosphorus-nitrogen bond length in P-Leu-NH2 is 0.18 nm, suggesting that the nitrogen is protonated whereas the same bond in phosphoramidon is much shorter (0.15 nm) suggesting that the nitrogen does not carry a charge. In phosphoramidon the distance from the phosphoramide nitrogen to Glu-143 is 0.39 nm whereas in P-Leu-NH2 this distance decreases to 0.34 nm. Taken together, these observations provide additional evidence in support of the participation of pentacoordinate intermediates in the mechanism of action of thermolysin [Holmes, M. A. and Matthews, B. W. (1981) Biochemistry 20, 6912-6920] and the role of Glu-143 in first promoting the attack of a water molecule on the carbonyl carbon of the scissile bond and subsequently acting as a 'proton shuttle' to transfer the proton to the leaving nitrogen [Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5724-5729; Hangauer, D. G., Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5730-5741].


==Overview==
Crystallographic structural analysis of phosphoramidates as inhibitors and transition-state analogs of thermolysin.,Tronrud DE, Monzingo AF, Matthews BW Eur J Biochem. 1986 Jun 2;157(2):261-8. PMID:3709536<ref>PMID:3709536</ref>
The mode of binding to thermolysin of the unsubstituted phosphoramidate inhibitor N-phosphoryl-L-leucinamide (P-Leu-NH2) has been determined crystallographically and refined at high resolution (R = 17.9% to 0.16-nm resolution). The mode of binding of the naturally occurring thermolysin inhibitor phosphoramidon reported previously [Weaver, L. H., Kester, W. R. and Matthews, B. W. (1977) J. Mol. Biol. 114, 119-132] has also been confirmed by crystallographic refinement (R = 17.4% to 0.23-nm resolution). Phosphoramidon binds to the enzyme with a single oxygen of the phosphoramidate moiety as a zinc ligand. Together with three ligands to the metal from the protein the resultant complex has approximately tetrahedral geometry. However, in the case of P-Leu-NH2, two of the phosphoramidate oxygens interact with the zinc to form a complex that tends towards pentacoordinate. In this respect, P-Leu-NH2 appears to be a better transition-state analog than is phosphoramidon. In addition, the phosphorus-nitrogen bond length in P-Leu-NH2 is 0.18 nm, suggesting that the nitrogen is protonated whereas the same bond in phosphoramidon is much shorter (0.15 nm) suggesting that the nitrogen does not carry a charge. In phosphoramidon the distance from the phosphoramide nitrogen to Glu-143 is 0.39 nm whereas in P-Leu-NH2 this distance decreases to 0.34 nm. Taken together, these observations provide additional evidence in support of the participation of pentacoordinate intermediates in the mechanism of action of thermolysin [Holmes, M. A. and Matthews, B. W. (1981) Biochemistry 20, 6912-6920] and the role of Glu-143 in first promoting the attack of a water molecule on the carbonyl carbon of the scissile bond and subsequently acting as a 'proton shuttle' to transfer the proton to the leaving nitrogen [Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5724-5729; Hangauer, D. G., Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5730-5741].


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


==Reference==
==See Also==
Crystallographic structural analysis of phosphoramidates as inhibitors and transition-state analogs of thermolysin., Tronrud DE, Monzingo AF, Matthews BW, Eur J Biochem. 1986 Jun 2;157(2):261-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/3709536 3709536]
*[[Thermolysin 3D structures|Thermolysin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bacillus thermoproteolyticus]]
[[Category: Bacillus thermoproteolyticus]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Thermolysin]]
[[Category: Matthews BW]]
[[Category: Matthews, B W.]]
[[Category: Monzingo AF]]
[[Category: Monzingo, A F.]]
[[Category: Tronrud DE]]
[[Category: Tronrud, D E.]]
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