7log: Difference between revisions
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<StructureSection load='7log' size='340' side='right'caption='[[7log]], [[Resolution|resolution]] 0.99Å' scene=''> | <StructureSection load='7log' size='340' side='right'caption='[[7log]], [[Resolution|resolution]] 0.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7log]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[7log]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LOG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LOG FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene>, <scene name='pdbligand=Y8J:3-butylpyridine'>Y8J</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.99Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene>, <scene name='pdbligand=Y8J:3-butylpyridine'>Y8J</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=7log FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7log OCA], [https://pdbe.org/7log PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7log RCSB], [https://www.ebi.ac.uk/pdbsum/7log PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7log ProSAT]</span></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=7log FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7log OCA], [https://pdbe.org/7log PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7log RCSB], [https://www.ebi.ac.uk/pdbsum/7log PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7log ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/D9IEF7_BPT4 D9IEF7_BPT4] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Escherichia virus T4]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Balius TE]] | |||
[[Category: Balius | [[Category: Kamenik AS]] | ||
[[Category: Kamenik | [[Category: Lak P]] | ||
[[Category: Lak | [[Category: Liedl KR]] | ||
[[Category: Liedl | [[Category: Shoichet BK]] | ||
[[Category: Shoichet | [[Category: Singh I]] | ||
[[Category: Singh | |||
Latest revision as of 18:54, 18 October 2023
T4 lysozyme mutant L99A in complex with 3-butylpyridineT4 lysozyme mutant L99A in complex with 3-butylpyridine
Structural highlights
FunctionPublication Abstract from PubMedProtein flexibility remains a major challenge in library docking because of difficulties in sampling conformational ensembles with accurate probabilities. Here, we use the model cavity site of T4 lysozyme L99A to test flexible receptor docking with energy penalties from molecular dynamics (MD) simulations. Crystallography with larger and smaller ligands indicates that this cavity can adopt three major conformations: open, intermediate, and closed. Since smaller ligands typically bind better to the cavity site, we anticipate an energy penalty for the cavity opening. To estimate its magnitude, we calculate conformational preferences from MD simulations. We find that including a penalty term is essential for retrospective ligand enrichment; otherwise, high-energy states dominate the docking. We then prospectively docked a library of over 900,000 compounds for new molecules binding to each conformational state. Absent a penalty term, the open conformation dominated the docking results; inclusion of this term led to a balanced sampling of ligands against each state. High ranked molecules were experimentally tested by Tm upshift and X-ray crystallography. From 33 selected molecules, we identified 18 ligands and determined 13 crystal structures. Most interesting were those bound to the open cavity, where the buried site opens to bulk solvent. Here, highly unusual ligands for this cavity had been predicted, including large ligands with polar tails; these were confirmed both by binding and by crystallography. In docking, incorporating protein flexibility with thermodynamic weightings may thus access new ligand chemotypes. The MD approach to accessing and, crucially, weighting such alternative states may find general applicability. Energy penalties enhance flexible receptor docking in a model cavity.,Kamenik AS, Singh I, Lak P, Balius TE, Liedl KR, Shoichet BK Proc Natl Acad Sci U S A. 2021 Sep 7;118(36). pii: 2106195118. doi:, 10.1073/pnas.2106195118. PMID:34475217[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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