6tx7: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==CRYSTAL STRUCTURE OF HUMAN FKBP51 FK1 DOMAIN A19T MUTANT IN COMPLEX WITH 2-PIPERIDONE== | ==CRYSTAL STRUCTURE OF HUMAN FKBP51 FK1 DOMAIN A19T MUTANT IN COMPLEX WITH 2-PIPERIDONE== | ||
<StructureSection load='6tx7' size='340' side='right'caption='[[6tx7]]' scene=''> | <StructureSection load='6tx7' size='340' side='right'caption='[[6tx7]], [[Resolution|resolution]] 1.13Å' 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=6TX7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TX7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6tx7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TX7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TX7 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tx7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tx7 OCA], [http://pdbe.org/6tx7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tx7 RCSB], [http://www.ebi.ac.uk/pdbsum/6tx7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tx7 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=V1L:piperidin-2-one'>V1L</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FKBP5, AIG6, FKBP51 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tx7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tx7 OCA], [http://pdbe.org/6tx7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tx7 RCSB], [http://www.ebi.ac.uk/pdbsum/6tx7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tx7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/FKBP5_HUMAN FKBP5_HUMAN]] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fragment-based drug discovery (FBDD) deploys efficient sampling of the vast chemical space for hit identification. Libraries are screened biophysically and fragment:protein co-structures are determined by X-ray crystallography. In parallel, computational methods can derive pharmacophore models or screen virtual libraries. We screened 15 very small fragments (VSFs) (HA <= 11) computationally, using site-identification by ligand competitive saturation (SILCS), and experimentally, by X-ray crystallography, to map potential interaction sites on the FKBP51 FK1 domain. We identified three hot spots and obtained 6 X-ray co-structures, giving a hit rate of 40%. SILCS FragMaps overlapped with X-ray structures. The compounds had millimolar affinities as determined by (15)N HSQC NMR. VSFs identified the same interactions as known FK1 binder and provide new chemical starting points. We propose a hybrid screening strategy starting with SILCS, followed by a pharmacophore-derived X-ray screen and (15)N HSQC NMR based KD determination to rapidly identify hits and their binding poses. | |||
A hybrid screening approach for very small fragments - X-ray and Computational Screening on FKBP51.,Draxler SW, Bauer M, Eickmeier C, Nadal S, Nar H, Rangel D, Seeliger D, Zeeb M, Fiegen D J Med Chem. 2020 May 18. doi: 10.1021/acs.jmedchem.0c00120. PMID:32420743<ref>PMID:32420743</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tx7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Draxler | [[Category: Peptidylprolyl isomerase]] | ||
[[Category: Fiegen D]] | [[Category: Draxler, S W]] | ||
[[Category: Fiegen, D]] | |||
[[Category: Fragment]] | |||
[[Category: Isomerase]] | |||
[[Category: Ppiase]] | |||
Revision as of 13:41, 17 June 2020
CRYSTAL STRUCTURE OF HUMAN FKBP51 FK1 DOMAIN A19T MUTANT IN COMPLEX WITH 2-PIPERIDONECRYSTAL STRUCTURE OF HUMAN FKBP51 FK1 DOMAIN A19T MUTANT IN COMPLEX WITH 2-PIPERIDONE
Structural highlights
Function[FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMedFragment-based drug discovery (FBDD) deploys efficient sampling of the vast chemical space for hit identification. Libraries are screened biophysically and fragment:protein co-structures are determined by X-ray crystallography. In parallel, computational methods can derive pharmacophore models or screen virtual libraries. We screened 15 very small fragments (VSFs) (HA <= 11) computationally, using site-identification by ligand competitive saturation (SILCS), and experimentally, by X-ray crystallography, to map potential interaction sites on the FKBP51 FK1 domain. We identified three hot spots and obtained 6 X-ray co-structures, giving a hit rate of 40%. SILCS FragMaps overlapped with X-ray structures. The compounds had millimolar affinities as determined by (15)N HSQC NMR. VSFs identified the same interactions as known FK1 binder and provide new chemical starting points. We propose a hybrid screening strategy starting with SILCS, followed by a pharmacophore-derived X-ray screen and (15)N HSQC NMR based KD determination to rapidly identify hits and their binding poses. A hybrid screening approach for very small fragments - X-ray and Computational Screening on FKBP51.,Draxler SW, Bauer M, Eickmeier C, Nadal S, Nar H, Rangel D, Seeliger D, Zeeb M, Fiegen D J Med Chem. 2020 May 18. doi: 10.1021/acs.jmedchem.0c00120. PMID:32420743[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||