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5od7

From Proteopedia

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Hsp90 inhibitor desolvation as a rationale to steer on-rates and impact residence time

Structural highlights

5od7 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 2Å
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

Residence time and more recently the association rate constant kon are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure-kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant kon decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.

Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors.,Schuetz DA, Richter L, Amaral M, Grandits M, Gradler U, Musil D, Buchstaller HP, Eggenweiler HM, Frech M, Ecker GF J Med Chem. 2018 May 10. doi: 10.1021/acs.jmedchem.8b00080. PMID:29701469^[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
↑ Schuetz DA, Richter L, Amaral M, Grandits M, Gradler U, Musil D, Buchstaller HP, Eggenweiler HM, Frech M, Ecker GF. Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors. J Med Chem. 2018 May 10. doi: 10.1021/acs.jmedchem.8b00080. PMID:29701469 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00080

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/5od7"

@@ Line 3: / Line 3: @@
 <StructureSection load='5od7' size='340' side='right'caption='[[5od7]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5od7]] 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=5OD7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OD7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5od7]] 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=5OD7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OD7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H0T:[2-azanyl-6-[2-(4-methylpiperazin-1-yl)sulfonylphenyl]quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone'>H0T</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]] 2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1, HSP90A, HSPC1, HSPCA ([http://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=H0T:[2-azanyl-6-[2-(4-methylpiperazin-1-yl)sulfonylphenyl]quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone'>H0T</scene></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=5od7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5od7 OCA], [http://pdbe.org/5od7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5od7 RCSB], [http://www.ebi.ac.uk/pdbsum/5od7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5od7 ProSAT]</span></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=5od7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5od7 OCA], [https://pdbe.org/5od7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5od7 RCSB], [https://www.ebi.ac.uk/pdbsum/5od7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5od7 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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 5od7" 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: Amaral, M]]
+[[Category: Amaral M]]
-[[Category: Buchstaller, H P]]
+[[Category: Buchstaller H-P]]
-[[Category: Ecker, G F]]
+[[Category: Ecker GF]]
-[[Category: Eggenweiler, H M]]
+[[Category: Eggenweiler H-M]]
-[[Category: Frech, M]]
+[[Category: Frech M]]
-[[Category: Graedler, U]]
+[[Category: Graedler U]]
-[[Category: Grandits, M]]
+[[Category: Grandits M]]
-[[Category: Lehmann, M]]
+[[Category: Lehmann M]]
-[[Category: Musil, D]]
+[[Category: Musil D]]
-[[Category: Richter, L]]
+[[Category: Richter L]]
-[[Category: Schuetz, D A]]
+[[Category: Schuetz DA]]
-[[Category: Atp-binding]]
-[[Category: Atpase]]
-[[Category: Chaperone]]
-[[Category: Heat shock]]
-[[Category: Heat-shock protein complex]]
-[[Category: Hsp90]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphorylation]]
-[[Category: Pyrazole]]

5od7

From Proteopedia

Current revision

Hsp90 inhibitor desolvation as a rationale to steer on-rates and impact residence time

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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