6sy3: Difference between revisions
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==Cationic Trypsin in Complex with a D-DiPhe-Pro-pyridine derivative== | ==Cationic Trypsin in Complex with a D-DiPhe-Pro-pyridine derivative== | ||
<StructureSection load='6sy3' size='340' side='right'caption='[[6sy3]]' scene=''> | <StructureSection load='6sy3' size='340' side='right'caption='[[6sy3]], [[Resolution|resolution]] 0.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SY3 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6sy3]] 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=6SY3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SY3 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.95Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=LXW:(2~{S})-1-[(2~{R})-2-azanyl-3,3-diphenyl-propanoyl]-~{N}-(pyridin-4-ylmethyl)pyrrolidine-2-carboxamide'>LXW</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=6sy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sy3 OCA], [https://pdbe.org/6sy3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6sy3 RCSB], [https://www.ebi.ac.uk/pdbsum/6sy3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6sy3 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/TRY1_BOVIN TRY1_BOVIN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Trypsin and thrombin, structurally similar serine proteases, recognize different substrates; thrombin cleaves after Arg, whereas trypsin cleaves after Lys/Arg. Both recognize basic substrate headgroups via Asp189 at the bottom of the S1 pocket. By crystallography and isothermal titration calorimetry (ITC), we studied a series of d-Phe/d-DiPhe-Pro-(amino)pyridines. Identical ligand pairs show the same binding poses. Surprisingly, one ligand binds to trypsin in protonated state and to thrombin in unprotonated state at P1 along with differences in the residual solvation pattern. While trypsin binding is mediated by an ordered water molecule, in thrombin, water is scattered over three hydration sites. Although having highly similar S1 pockets, our results suggest different electrostatic properties of Asp189 possibly contributing to the selectivity determinant. Thrombin binds a specific Na(+) ion next to Asp189, which is absent in trypsin. The electrostatic properties across the S1 pocket are further attenuated by charged Glu192 at the rim of S1 in thrombin, which is replaced by uncharged Gln192 in trypsin. | |||
Protein-Induced Change in Ligand Protonation during Trypsin and Thrombin Binding: Hint on Differences in Selectivity Determinants of Both Proteins?,Ngo K, Collins-Kautz C, Gerstenecker S, Wagner B, Heine A, Klebe G J Med Chem. 2020 Mar 26;63(6):3274-3289. doi: 10.1021/acs.jmedchem.9b02061. Epub , 2020 Feb 24. PMID:32011145<ref>PMID:32011145</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6sy3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Trypsin 3D structures|Trypsin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Heine A]] | [[Category: Heine A]] | ||
[[Category: Klebe G]] | [[Category: Klebe G]] | ||
[[Category: Ngo K]] | [[Category: Ngo K]] | ||
Latest revision as of 15:50, 24 January 2024
Cationic Trypsin in Complex with a D-DiPhe-Pro-pyridine derivativeCationic Trypsin in Complex with a D-DiPhe-Pro-pyridine derivative
Structural highlights
FunctionPublication Abstract from PubMedTrypsin and thrombin, structurally similar serine proteases, recognize different substrates; thrombin cleaves after Arg, whereas trypsin cleaves after Lys/Arg. Both recognize basic substrate headgroups via Asp189 at the bottom of the S1 pocket. By crystallography and isothermal titration calorimetry (ITC), we studied a series of d-Phe/d-DiPhe-Pro-(amino)pyridines. Identical ligand pairs show the same binding poses. Surprisingly, one ligand binds to trypsin in protonated state and to thrombin in unprotonated state at P1 along with differences in the residual solvation pattern. While trypsin binding is mediated by an ordered water molecule, in thrombin, water is scattered over three hydration sites. Although having highly similar S1 pockets, our results suggest different electrostatic properties of Asp189 possibly contributing to the selectivity determinant. Thrombin binds a specific Na(+) ion next to Asp189, which is absent in trypsin. The electrostatic properties across the S1 pocket are further attenuated by charged Glu192 at the rim of S1 in thrombin, which is replaced by uncharged Gln192 in trypsin. Protein-Induced Change in Ligand Protonation during Trypsin and Thrombin Binding: Hint on Differences in Selectivity Determinants of Both Proteins?,Ngo K, Collins-Kautz C, Gerstenecker S, Wagner B, Heine A, Klebe G J Med Chem. 2020 Mar 26;63(6):3274-3289. doi: 10.1021/acs.jmedchem.9b02061. Epub , 2020 Feb 24. PMID:32011145[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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