5m4h

From Proteopedia

(Difference between revisions)

Revision as of 07:17, 6 November 2019

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

Structural highlights

5m4h 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

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1alpha subunit in the PC3 cancer cell line in vitro.

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.,Brough PA, Baker L, Bedford S, Brown K, Chavda S, Chell V, D'Alessandro J, Davies NG, Davis B, Le Strat L, Macias AT, Maddox D, Mahon PC, Massey AJ, Matassova N, McKenna S, Moore JD, Murray JB, Northfield CJ, Parry C, Parsons R, Roughley SD, Shaw T, Simmonite H, Stokes S, Surgenor A, Stefaniak E, Robertson A, Wang Y, Webb P, Whitehead N, Wood M J Med Chem. 2017 Feb 15. doi: 10.1021/acs.jmedchem.6b01478. PMID:28199108^[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
↑ Brough PA, Baker L, Bedford S, Brown K, Chavda S, Chell V, D'Alessandro J, Davies NG, Davis B, Le Strat L, Macias AT, Maddox D, Mahon PC, Massey AJ, Matassova N, McKenna S, Moore JD, Murray JB, Northfield CJ, Parry C, Parsons R, Roughley SD, Shaw T, Simmonite H, Stokes S, Surgenor A, Stefaniak E, Robertson A, Wang Y, Webb P, Whitehead N, Wood M. Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase. J Med Chem. 2017 Feb 15. doi: 10.1021/acs.jmedchem.6b01478. PMID:28199108 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01478

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/5m4h"

@@ Line 1: / Line 1: @@
 ==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase==
-<StructureSection load='5m4h' size='340' side='right' caption='[[5m4h]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='5m4h' size='340' side='right'caption='[[5m4h]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5m4h]] 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=5M4H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4H 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: Baker, L M]]
 [[Category: Brough, P]]

5m4h

From Proteopedia

Revision as of 07:17, 6 November 2019

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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