2y57: Difference between revisions
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< | ==Fragment growing induces conformational changes in acetylcholine- binding protein: A structural and thermodynamic analysis - (Compound 4)== | ||
<StructureSection load='2y57' size='340' side='right'caption='[[2y57]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2y57]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Aplysia_californica Aplysia californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y57 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]] 3.3Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=V37:[(1R,5S)-8-PHENETHYL-8-AZABICYCLO[3.2.1]OCTAN-3-YL]+BENZOATE'>V37</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=2y57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y57 OCA], [https://pdbe.org/2y57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y57 RCSB], [https://www.ebi.ac.uk/pdbsum/2y57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y57 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q8WSF8_APLCA Q8WSF8_APLCA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The fragment optimization was monitored with X-ray structures of ligand complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis and isothermal titration calorimetry (ITC). Using site-directed mutagenesis and AChBP from different species, we find that specific changes in thermodynamic binding profiles, are indicative of interactions with the ligand-inducible subpocket of AChBP. This study illustrates that thermodynamic analysis provides valuable information on ligand binding modes and is complementary to affinity data when guiding rational structure- and fragment-based discovery approaches. | |||
Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis.,Edink E, Rucktooa P, Retra K, Akdemir A, Nahar T, Zuiderveld O, van Elk R, Janssen E, van Nierop P, van Muijlwijk-Koezen J, Smit AB, Sixma TK, Leurs R, de Esch IJ J Am Chem Soc. 2011 Apr 13;133(14):5363-71. Epub 2011 Feb 15. PMID:21322593<ref>PMID:21322593</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2y57" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Acetylcholine binding protein 3D structures|Acetylcholine binding protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Aplysia californica]] | [[Category: Aplysia californica]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Edink | [[Category: Edink E]] | ||
[[Category: Rucktooa | [[Category: Rucktooa P]] | ||
[[Category: Sixma | [[Category: Sixma TK]] | ||
[[Category: | [[Category: DeEsch IJP]] | ||
Latest revision as of 11:08, 23 August 2023
Fragment growing induces conformational changes in acetylcholine- binding protein: A structural and thermodynamic analysis - (Compound 4)Fragment growing induces conformational changes in acetylcholine- binding protein: A structural and thermodynamic analysis - (Compound 4)
Structural highlights
FunctionPublication Abstract from PubMedOptimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The fragment optimization was monitored with X-ray structures of ligand complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis and isothermal titration calorimetry (ITC). Using site-directed mutagenesis and AChBP from different species, we find that specific changes in thermodynamic binding profiles, are indicative of interactions with the ligand-inducible subpocket of AChBP. This study illustrates that thermodynamic analysis provides valuable information on ligand binding modes and is complementary to affinity data when guiding rational structure- and fragment-based discovery approaches. Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis.,Edink E, Rucktooa P, Retra K, Akdemir A, Nahar T, Zuiderveld O, van Elk R, Janssen E, van Nierop P, van Muijlwijk-Koezen J, Smit AB, Sixma TK, Leurs R, de Esch IJ J Am Chem Soc. 2011 Apr 13;133(14):5363-71. Epub 2011 Feb 15. PMID:21322593[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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