View source for 7ph1


==Trypsin in complex with BPTI mutant (2S)-2-amino-4-monofluorobutanoic acid==
<StructureSection load='7ph1' size='340' side='right'caption='[[7ph1]], [[Resolution|resolution]] 1.18&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ph1]] is a 2 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=7PH1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PH1 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]] 1.18&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7OZ:(S)-2-amino-4-fluorobutanoic+acid'>7OZ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7ph1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ph1 OCA], [https://pdbe.org/7ph1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ph1 RCSB], [https://www.ebi.ac.uk/pdbsum/7ph1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ph1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TRY1_BOVIN TRY1_BOVIN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural waters in the S1 binding pocket of beta-trypsin are critical for the stabilization of the complex of beta-trypsin with its inhibitor bovine pancreatic trypsin inhibitor (BPTI). The inhibitor strength of BPTI can be modulated by replacing the critical lysine residue at the P1 position by non-natural amino acids. We study BPTI variants in which the critical Lys15 in BPTI has been replaced by alpha-aminobutyric acid (Abu) and its fluorinated derivatives monofluoroethylglycine (MfeGly), difluoroethylglycine (DfeGly), and trifluoroethylglycine (TfeGly). We investigate the hypothesis that additional water molecules in the binding pocket can form specific noncovalent interactions with the fluorinated side chains and thereby act as an extension of the inhibitors. We report potentials of mean force (PMF) of the unbinding process for all four complexes and enzyme activity inhibition assays. Additionally, we report the protein crystal structure of the Lys15MfeGly-BPTI-beta-trypsin complex (pdb: 7PH1). Both experimental and computational data show a stepwise increase in inhibitor strength with increasing fluorination of the Abu side chain. The PMF additionally shows a minimum for the encounter complex and an intermediate state just before the bound state. In the bound state, the computational analysis of the structure and dynamics of the water molecules in the S1 pocket shows a highly dynamic network of water molecules that does not indicate a rigidification or stabilizing trend in regard to energetic properties that could explain the increase in inhibitor strength. The analysis of the energy and the entropy of the water molecules in the S1 binding pocket using grid inhomogeneous solvation theory confirms this result. Overall, fluorination systematically changes the binding affinity, but the effect cannot be explained by a persistent water network in the binding pocket. Other effects, such as the hydrophobicity of fluorinated amino acids and the stability of the encounter complex as well as the additional minimum in the potential of mean force in the bound state, likely influence the affinity more directly.

Water Network in the Binding Pocket of Fluorinated BPTI-Trypsin Complexes horizontal line Insights from Simulation and Experiment.,Wehrhan L, Leppkes J, Dimos N, Loll B, Koksch B, Keller BG J Phys Chem B. 2022 Nov 21. doi: 10.1021/acs.jpcb.2c05496. PMID:36409613<ref>PMID:36409613</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ph1" style="background-color:#fffaf0;"></div>

==See Also==
*[[BPTI 3D structures|BPTI 3D structures]]
*[[Trypsin 3D structures|Trypsin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Large Structures]]
[[Category: Dimos N]]
[[Category: Koksch B]]
[[Category: Leppkes J]]
[[Category: Loll B]]