View source for 7q96


==Keap1 compound complex==
<StructureSection load='7q96' size='340' side='right'caption='[[7q96]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7q96]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q96 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]] 2.415&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9P0:4-[(5S,8R)-5-(dimethylcarbamoyl)-8-[[(2S)-1-ethanoylpyrrolidin-2-yl]carbonylamino]-7,11-bis(oxidanylidene)-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-trien-16-yl]benzoic+acid'>9P0</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=7q96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q96 OCA], [https://pdbe.org/7q96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q96 RCSB], [https://www.ebi.ac.uk/pdbsum/7q96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q96 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KEAP1_HUMAN KEAP1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.

Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction.,Begnini F, Geschwindner S, Johansson P, Wissler L, Lewis RJ, Danelius E, Luttens A, Matricon P, Carlsson J, Lenders S, Konig B, Friedel A, Sjo P, Schiesser S, Kihlberg J J Med Chem. 2022 Feb 24;65(4):3473-3517. doi: 10.1021/acs.jmedchem.1c01975. Epub , 2022 Feb 2. PMID:35108001<ref>PMID:35108001</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7q96" style="background-color:#fffaf0;"></div>

==See Also==
*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Johansson P]]