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==Crystal Structure of CPA and sulfamide-based inhibitor complex== | |||
<StructureSection load='1iy7' size='340' side='right'caption='[[1iy7]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1iy7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1IY7 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=CXA:PHENYLALANINE-N-SULFONAMIDE'>CXA</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=1iy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1iy7 OCA], [https://pdbe.org/1iy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1iy7 RCSB], [https://www.ebi.ac.uk/pdbsum/1iy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1iy7 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CBPA1_BOVIN CBPA1_BOVIN] Carboxypeptidase that catalyzes the release of a C-terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro (By similarity). | |||
== 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/iy/1iy7_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=1iy7 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
N-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on the terminal amino group were designed rationally as transition state analogue inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA inhibitory assays the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent inhibitory activity with the K(i) value of 0.64 microM. Its enantiomer was shown to be much less potent (K(i) = 470 microM). Introduction of an alkyl group such as methyl or isopropyl group on the terminal amino group of (S)-1a lowered the inhibitory potency drastically. Introduction of a methyl group on the internal amino group of (S)-1a also caused a drastic reduction of the inhibitory activity. The structure of the CPA x(S)-1a complex determined by single-crystal X-ray diffraction reveals that the sulfamoyl moiety interacts with the zinc ion and functional groups at the active site of CPA, which is reminiscent of the postulated stabilization mode of a tetrahedral transition state in the CPA-catalyzed hydrolysis of a peptide substrate. On the basis of the design rationale and the binding mode of (S)-1a to CPA shown by X-ray crystallographic analysis, the present inhibitors are inferred to be a novel type of transition state analogue inhibitor for CPA. | |||
Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.,Park JD, Kim DH, Kim SJ, Woo JR, Ryu SE J Med Chem. 2002 Nov 21;45(24):5295-302. PMID:12431056<ref>PMID:12431056</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1iy7" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Kim DH]] | |||
[[Category: Kim | [[Category: Kim SJ]] | ||
[[Category: Kim | [[Category: Park JD]] | ||
[[Category: Park | [[Category: Ryu SE]] | ||
[[Category: Ryu | [[Category: Woo JR]] | ||
[[Category: Woo | |||
Latest revision as of 10:27, 23 October 2024
Crystal Structure of CPA and sulfamide-based inhibitor complexCrystal Structure of CPA and sulfamide-based inhibitor complex
Structural highlights
FunctionCBPA1_BOVIN Carboxypeptidase that catalyzes the release of a C-terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro (By similarity). 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 PubMedN-Sulfamoylphenylalanine and its derivatives having varied alkyl groups on the terminal amino group were designed rationally as transition state analogue inhibitors for carboxypeptidase A (CPA) and synthesized. In CPA inhibitory assays the parent compound having the (S)-configuration, i.e., (S)-1a, showed potent inhibitory activity with the K(i) value of 0.64 microM. Its enantiomer was shown to be much less potent (K(i) = 470 microM). Introduction of an alkyl group such as methyl or isopropyl group on the terminal amino group of (S)-1a lowered the inhibitory potency drastically. Introduction of a methyl group on the internal amino group of (S)-1a also caused a drastic reduction of the inhibitory activity. The structure of the CPA x(S)-1a complex determined by single-crystal X-ray diffraction reveals that the sulfamoyl moiety interacts with the zinc ion and functional groups at the active site of CPA, which is reminiscent of the postulated stabilization mode of a tetrahedral transition state in the CPA-catalyzed hydrolysis of a peptide substrate. On the basis of the design rationale and the binding mode of (S)-1a to CPA shown by X-ray crystallographic analysis, the present inhibitors are inferred to be a novel type of transition state analogue inhibitor for CPA. Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.,Park JD, Kim DH, Kim SJ, Woo JR, Ryu SE J Med Chem. 2002 Nov 21;45(24):5295-302. PMID:12431056[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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