View source for 6lt8


==HSP90 in complex with KW-2478==
<StructureSection load='6lt8' size='340' side='right'caption='[[6lt8]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6lt8]] is a 1 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=6LT8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LT8 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]] 1.593&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ET3:2-[2-ethyl-6-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]carbonyl-3,5-bis(oxidanyl)phenyl]-~{N},~{N}-bis(2-methoxyethyl)ethanamide'>ET3</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=6lt8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lt8 OCA], [https://pdbe.org/6lt8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lt8 RCSB], [https://www.ebi.ac.uk/pdbsum/6lt8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lt8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 (N) (Hsp90(N)). Absence of complex crystal structure of Hsp90(N)-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90(N)-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 A; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, DeltaTm, 18.82 +/- 0.51 degrees C) and isothermal titration calorimetry (ITC, Kd, 7.30 +/- 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90(N). Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 muM for A549; 14.29 muM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90(N)-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90(N) evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.

Anti-NSCLC activity in vitro of Hsp90(N) inhibitor KW-2478 and complex crystal structure determination of Hsp90(N)-KW-2478.,Li HJ, Wang QS, Han W, Zhou H, Li P, Zhou F, Qin W, Zhao D, Zhou X, He CX, Xing L, Li PQ, Jin X, Yu F, He JH, Cao HL J Struct Biol. 2021 Jun;213(2):107710. doi: 10.1016/j.jsb.2021.107710. Epub 2021 , Feb 19. PMID:33610655<ref>PMID:33610655</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6lt8" style="background-color:#fffaf0;"></div>

==See Also==
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cao HL]]