5aqy

From Proteopedia

(Difference between revisions)

Current revision

Fragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues

Structural highlights

5aqy 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 1.56Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HS71A_HUMAN In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).^[1] ^[2] ^[3]

Publication Abstract from PubMed

The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.

A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.,Jones AM, Westwood IM, Osborne JD, Matthews TP, Cheeseman MD, Rowlands MG, Jeganathan F, Burke R, Lee D, Kadi N, Liu M, Richards M, McAndrew C, Yahya N, Dobson SE, Jones K, Workman P, Collins I, van Montfort RL Sci Rep. 2016 Oct 6;6:34701. doi: 10.1038/srep34701. PMID:27708405^[4]

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

References

↑ Perez-Vargas J, Romero P, Lopez S, Arias CF. The peptide-binding and ATPase domains of recombinant hsc70 are required to interact with rotavirus and reduce its infectivity. J Virol. 2006 Apr;80(7):3322-31. PMID:16537599 doi:http://dx.doi.org/80/7/3322
↑ Liu X, Liu D, Qian D, Dai J, An Y, Jiang S, Stanley B, Yang J, Wang B, Liu X, Liu DX. Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. J Biol Chem. 2012 Jun 1;287(23):19599-609. doi: 10.1074/jbc.M112.363622. Epub, 2012 Apr 23. PMID:22528486 doi:http://dx.doi.org/10.1074/jbc.M112.363622
↑ Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park BV, Pan Z, Zhang J, Dang E, Li Z, Wang H, Luo W, Li L, Semenza GL, Zheng SG, Loser K, Tsun A, Greene MI, Pardoll DM, Pan F, Li B. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity. 2013 Aug 22;39(2):272-85. doi: 10.1016/j.immuni.2013.08.006. PMID:23973223 doi:http://dx.doi.org/10.1016/j.immuni.2013.08.006
↑ Jones AM, Westwood IM, Osborne JD, Matthews TP, Cheeseman MD, Rowlands MG, Jeganathan F, Burke R, Lee D, Kadi N, Liu M, Richards M, McAndrew C, Yahya N, Dobson SE, Jones K, Workman P, Collins I, van Montfort RL. A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms. Sci Rep. 2016 Oct 6;6:34701. doi: 10.1038/srep34701. PMID:27708405 doi:http://dx.doi.org/10.1038/srep34701

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/5aqy"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5aqy is ON HOLD  until Paper Publication
+==Fragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues==
+<StructureSection load='5aqy' size='340' side='right'caption='[[5aqy]], [[Resolution|resolution]] 1.56&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5aqy]] 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=5AQY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AQY 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]] 1.56&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADN:ADENOSINE'>ADN</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5aqy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aqy OCA], [https://pdbe.org/5aqy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aqy RCSB], [https://www.ebi.ac.uk/pdbsum/5aqy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aqy ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.
-Authors: Jones, A.M., Westwood, I.M., Osborne, J.D., Matthews, T.P., Cheeseman, M.D., Rowlands, M.G., Jeganathan, F., Burke, R., Lee, D., Kadi, N., Liu, M., Richards, M., McAndrew, C., Yahya, N., Dobson, S.E., Jones, K., Workman, P., Collins, I., van Montfort, R.L.M.
+A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.,Jones AM, Westwood IM, Osborne JD, Matthews TP, Cheeseman MD, Rowlands MG, Jeganathan F, Burke R, Lee D, Kadi N, Liu M, Richards M, McAndrew C, Yahya N, Dobson SE, Jones K, Workman P, Collins I, van Montfort RL Sci Rep. 2016 Oct 6;6:34701. doi: 10.1038/srep34701. PMID:27708405<ref>PMID:27708405</ref>
-Description: Fragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Burke, R]]
+<div class="pdbe-citations 5aqy" style="background-color:#fffaf0;"></div>
-[[Category: Liu, M]]
-[[Category: Van Montfort, R.L.M]]
+==See Also==
-[[Category: Yahya, N]]
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
-[[Category: Dobson, S.E]]
+== References ==
-[[Category: Collins, I]]
+<references/>
-[[Category: Workman, P]]
+__TOC__
-[[Category: Jones, K]]
+</StructureSection>
-[[Category: Cheeseman, M.D]]
+[[Category: Homo sapiens]]
-[[Category: Westwood, I.M]]
+[[Category: Large Structures]]
-[[Category: Jones, A.M]]
+[[Category: Burke R]]
-[[Category: Richards, M]]
+[[Category: Cheeseman MD]]
-[[Category: Lee, D]]
+[[Category: Collins I]]
-[[Category: Rowlands, M.G]]
+[[Category: Dobson SE]]
-[[Category: Mcandrew, C]]
+[[Category: Jeganathan F]]
-[[Category: Kadi, N]]
+[[Category: Jones AM]]
-[[Category: Jeganathan, F]]
+[[Category: Jones K]]
-[[Category: Osborne, J.D]]
+[[Category: Kadi N]]
-[[Category: Matthews, T.P]]
+[[Category: Lee D]]
+[[Category: Liu M]]
+[[Category: Matthews TP]]
+[[Category: McAndrew C]]
+[[Category: Osborne JD]]
+[[Category: Richards M]]
+[[Category: Rowlands MG]]
+[[Category: Westwood IM]]
+[[Category: Workman P]]
+[[Category: Yahya N]]
+[[Category: Van Montfort RLM]]

5aqy

From Proteopedia

Current revision

Fragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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