6lt8

From Proteopedia

(Difference between revisions)

Current revision

HSP90 in complex with KW-2478

Structural highlights

6lt8 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.593Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
↑ 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. Anti-NSCLC activity in vitro of Hsp90(N) inhibitor KW-2478 and complex crystal structure determination of Hsp90(N)-KW-2478. J Struct Biol. 2021 Jun;213(2):107710. doi: 10.1016/j.jsb.2021.107710. Epub 2021 , Feb 19. PMID:33610655 doi:http://dx.doi.org/10.1016/j.jsb.2021.107710

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6lt8"

Categories: Homo sapiens | Large Structures | Cao HL

@@ Line 3: / Line 3: @@
 <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/Human Human]. 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>
+<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='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>
+</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1, HSP90A, HSPC1, HSPCA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
+[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 ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6lt8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Cao, H L]]
+[[Category: Cao HL]]
-[[Category: Chaperone]]
-[[Category: Hsp90]]
-[[Category: Kw-2478]]

6lt8

From Proteopedia

Current revision

HSP90 in complex with KW-2478

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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