This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

6ceo

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 09:58, 4 December 2019

Structure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor.

Structural highlights

6ceo is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	HSP90AA1, HSP90A, HSPC1, HSPCA (HUMAN)
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

Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94.

Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.,Que NLS, Crowley VM, Duerfeldt AS, Zhao J, Kent CN, Blagg BSJ, Gewirth DT J Med Chem. 2018 Apr 12;61(7):2793-2805. doi: 10.1021/acs.jmedchem.7b01608. Epub , 2018 Mar 20. PMID:29528635^[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
↑ Que NLS, Crowley VM, Duerfeldt AS, Zhao J, Kent CN, Blagg BSJ, Gewirth DT. Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding. J Med Chem. 2018 Apr 12;61(7):2793-2805. doi: 10.1021/acs.jmedchem.7b01608. Epub , 2018 Mar 20. PMID:29528635 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01608

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/6ceo"

@@ Line 1: / Line 1: @@
 ==Structure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor.==
-<StructureSection load='6ceo' size='340' side='right' caption='[[6ceo]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='6ceo' size='340' side='right'caption='[[6ceo]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[6ceo]] 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=6CEO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CEO FirstGlance]. <br>
@@ Line 21: / Line 21: @@
 ==See Also==
-*[[Heat Shock Proteins|Heat Shock Proteins]]
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
 == References ==
 <references/>
@@ Line 27: / Line 27: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Gewirth, D T]]
 [[Category: Que, N L.S]]

6ceo

From Proteopedia

Revision as of 09:58, 4 December 2019

Structure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox