View source for 1bxq


==ACID PROTEINASE (PENICILLOPEPSIN) COMPLEX WITH PHOSPHONATE INHIBITOR.==
<StructureSection load='1bxq' size='340' side='right'caption='[[1bxq]], [[Resolution|resolution]] 1.41&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BXQ 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]] 1.41&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=PP8:2-[(1R)-1-(N-(3-METHYLBUTANOYL)-L-VALYL-L-ASPARAGINYL)-AMINO)-3-METHYLBUTYL]HYDROXYPHOSPHINYLOXY]-3-PHENYLPROPANOIC+ACID+METHYLESTER'>PP8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1bxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bxq OCA], [https://pdbe.org/1bxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bxq RCSB], [https://www.ebi.ac.uk/pdbsum/1bxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bxq ProSAT]</span></td></tr>
</table>
== 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/bx/1bxq_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1bxq ConSurf].
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== Publication Abstract from PubMed ==
The design of inhibitors with enhanced potency against proteolytic enzymes has many applications for the treatment of human diseases. In addition to the optimization of chemical interactions between the enzyme and inhibitor, the binding affinity can be increased by constraining the inhibitor to the conformation that is recognized by the enzyme, thus lowering the entropic barrier to complex formation. We have structurally characterized the complexes of a macrocyclic pentapeptide inhibitor and its acyclic analogue with penicillopepsin, an aspartic proteinase, to study the effect of conformational constraint on the binding affinity. The phosphonate-based macrocycle PPi4 (Ki = 0.10 nM) is covalently linked at the P2-Asn and P1'-Phe side chains [nomenclature of Schechter and Berger, Biochim. Biophys. Res. Commun. (1967) 27, 157-162] via an amide bond, relative to the acyclic compound PPi3 (Ki = 42 nM). Comparisons of the high-resolution crystal structures of PPi4-penicillopepsin (0.95 A) and PPi3-penicillopepsin (1.45 A) reveal that the conformations of the inhibitors and their interactions with the enzyme are similar. The 420-fold increase in the binding affinity of PPi4 is attributed to a reduction in its conformational flexibility, thus providing the first rigorous measure of the entropic contribution to the binding energy in a protein-ligand complex and stressing the advantages of the design strategy.

Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes.,Khan AR, Parrish JC, Fraser ME, Smith WW, Bartlett PA, James MN Biochemistry. 1998 Dec 1;37(48):16839-45. PMID:9836576<ref>PMID:9836576</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1bxq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Penicillopepsin|Penicillopepsin]]
*[[Pepsin|Pepsin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Bartlett PA]]
[[Category: Fraser ME]]
[[Category: James MNG]]
[[Category: Khan AR]]
[[Category: Parrish JC]]
[[Category: Smith WW]]