| Structural highlights
5aqk is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Related: | 5aqf, 5aqg, 5aqh, 5aqi, 5aqj, 5aql, 5aqm, 5aqn, 5aqo, 5aqp, 5aqq, 5aqr, 5aqs, 5aqt, 5aqu, 5aqv, 5aqw, 5aqx, 5aqy, 5aqz, 5ar0 |
| Activity: | Mitochondrial protein-transporting ATPase, with EC number 3.6.3.51 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[HSP7C_HUMAN] Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Chaperone. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex.[1] [BAG1_HUMAN] Inhibits the chaperone activity of HSP70/HSC70 by promoting substrate release. Inhibits the pro-apoptotic function of PPP1R15A, and has anti-apoptotic activity. Markedly increases the anti-cell death function of BCL2 induced by various stimuli.[2] [3] [4]
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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yahata T, de Caestecker MP, Lechleider RJ, Andriole S, Roberts AB, Isselbacher KJ, Shioda T. The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors. J Biol Chem. 2000 Mar 24;275(12):8825-34. PMID:10722728
- ↑ Takayama S, Bimston DN, Matsuzawa S, Freeman BC, Aime-Sempe C, Xie Z, Morimoto RI, Reed JC. BAG-1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J. 1997 Aug 15;16(16):4887-96. PMID:9305631 doi:http://dx.doi.org/10.1093/emboj/16.16.4887
- ↑ Takayama S, Xie Z, Reed JC. An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators. J Biol Chem. 1999 Jan 8;274(2):781-6. PMID:9873016
- ↑ Hung WJ, Roberson RS, Taft J, Wu DY. Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions. Mol Cell Biol. 2003 May;23(10):3477-86. PMID:12724406
- ↑ 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
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