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| | ==Predicting protein conformational response in prospective ligand discovery== | | ==Predicting protein conformational response in prospective ligand discovery== |
| - | <StructureSection load='4nvh' size='340' side='right' caption='[[4nvh]], [[Resolution|resolution]] 1.24Å' scene=''> | + | <StructureSection load='4nvh' size='340' side='right'caption='[[4nvh]], [[Resolution|resolution]] 1.24Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4nvh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NVH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NVH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4nvh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_RM11-1a Saccharomyces cerevisiae RM11-1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NVH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2NB:3-NITROQUINOLIN-4-AMINE'>2NB</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.24Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nva|4nva]], [[4nvb|4nvb]], [[4nvc|4nvc]], [[4nvd|4nvd]], [[4nve|4nve]], [[4nvf|4nvf]], [[4nvg|4nvg]], [[4nvi|4nvi]], [[4nvj|4nvj]], [[4nvk|4nvk]], [[4nvl|4nvl]], [[4nvm|4nvm]], [[4nvn|4nvn]], [[4nvo|4nvo]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2NB:3-NITROQUINOLIN-4-AMINE'>2NB</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CCP1 CCP CPO YKR066C, SCRG_04081 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=285006 Baker's yeast])</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=4nvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nvh OCA], [https://pdbe.org/4nvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nvh RCSB], [https://www.ebi.ac.uk/pdbsum/4nvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nvh ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nvh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nvh RCSB], [http://www.ebi.ac.uk/pdbsum/4nvh PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/B3LRE1_YEAS1 B3LRE1_YEAS1] |
| - | Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available.
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| - | Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery.,Fischer M, Coleman RG, Fraser JS, Shoichet BK Nat Chem. 2014 Jul;6(7):575-83. doi: 10.1038/nchem.1954. Epub 2014 May 25. PMID:24950326<ref>PMID:24950326</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| | ==See Also== | | ==See Also== |
| - | *[[Cytochrome c peroxidase|Cytochrome c peroxidase]] | + | *[[Cytochrome c peroxidase 3D structures|Cytochrome c peroxidase 3D structures]] |
| - | == References ==
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| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Baker's yeast]] | + | [[Category: Large Structures]] |
| - | [[Category: Fischer, M]] | + | [[Category: Saccharomyces cerevisiae RM11-1a]] |
| - | [[Category: Fraser, J S]] | + | [[Category: Fischer M]] |
| - | [[Category: Boltzmann weight]] | + | [[Category: Fraser JS]] |
| - | [[Category: Dynamic]]
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| - | [[Category: Energy penalty]]
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| - | [[Category: Flexibility]]
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| - | [[Category: Flexible docking]]
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| - | [[Category: Ligand binding]]
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| - | [[Category: Loop]]
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| - | [[Category: Model system]]
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| - | [[Category: Occupancy]]
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| - | [[Category: Oxidoreductase]]
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| - | [[Category: Side-chain]]
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