7lx9: Difference between revisions
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==T4 lysozyme mutant L99A== | ==T4 lysozyme mutant L99A== | ||
<StructureSection load='7lx9' size='340' side='right'caption='[[7lx9]]' scene=''> | <StructureSection load='7lx9' size='340' side='right'caption='[[7lx9]], [[Resolution|resolution]] 1.19Å' 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=7LX9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LX9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lx9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bpt4 Bpt4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LX9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LX9 FirstGlance]. <br> | ||
</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=7lx9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lx9 OCA], [https://pdbe.org/7lx9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lx9 RCSB], [https://www.ebi.ac.uk/pdbsum/7lx9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lx9 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene>, <scene name='pdbligand=YGM:(but-3-en-1-yl)benzene'>YGM</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">e, T4Tp126 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10665 BPT4])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </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=7lx9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lx9 OCA], [https://pdbe.org/7lx9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lx9 RCSB], [https://www.ebi.ac.uk/pdbsum/7lx9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lx9 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Protein 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<ref>PMID:34475217</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lx9" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Lysozyme 3D structures|Lysozyme 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bpt4]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Balius | [[Category: Lysozyme]] | ||
[[Category: Kamenik | [[Category: Balius, T E]] | ||
[[Category: Lak P]] | [[Category: Kamenik, A S]] | ||
[[Category: Liedl | [[Category: Lak, P]] | ||
[[Category: Shoichet | [[Category: Liedl, K R]] | ||
[[Category: Singh I]] | [[Category: Shoichet, B K]] | ||
[[Category: Singh, I]] | |||
[[Category: Complex]] | |||
[[Category: Hydrolase]] | |||
[[Category: L99a]] | |||
[[Category: Mutant]] | |||
[[Category: Protein binding]] | |||
[[Category: Small molecule]] | |||
Revision as of 13:07, 8 December 2021
T4 lysozyme mutant L99AT4 lysozyme mutant L99A
Structural highlights
Publication 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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