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5AQG

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

Summary for 5AQG
Entry DOI10.2210/pdb5aqg/pdb
Related5AQF 5AQH 5AQI 5AQJ 5AQK 5AQL 5AQM 5AQN 5AQO 5AQP 5AQQ 5AQR 5AQS 5AQT 5AQU 5AQV 5AQW 5AQX 5AQY 5AQZ 5AR0
DescriptorHEAT SHOCK COGNATE 71 KDA PROTEIN, BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1, (2R,3R,4S,5R)-2-(3-AMINO-5-METHYL-1,4,5,6,8-PENTAAZAACENAPHTHYLEN-1(5H)-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL, ... (7 entities in total)
Functional Keywordsheat shock protein, hsp70, hsp72, hsc70, atpase, bag1, chaperone, fragment
Biological sourceHOMO SAPIENS (HUMAN)
More
Cellular locationCytoplasm: P11142
Isoform 1: Nucleus. Isoform 2: Cytoplasm. Isoform 4: Cytoplasm: Q99933
Total number of polymer chains6
Total formula weight170136.88
Authors
Primary citationJones, 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.
A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.
Sci Rep, 6:34701-34701, 2016
Cited by
PubMed Abstract: 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.
PubMed: 27708405
DOI: 10.1038/srep34701
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.24 Å)
Structure validation

229183

건을2024-12-18부터공개중

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