5aqn | pdb_00005aqn

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

spinqualitylabelsall models 5aqn, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5aqn is a 6 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 2.45Å Ligands: CL, DMS, GOL, JG8, TRS 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

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