5AQH

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

Summary for 5AQH

• Entry DOI: 10.2210/pdb5aqh/pdb
• Related: 5AQF 5AQG 5AQI 5AQJ 5AQK 5AQL 5AQM 5AQN 5AQO 5AQP 5AQQ 5AQR 5AQS 5AQT 5AQU 5AQV 5AQW 5AQX 5AQY 5AQZ 5AR0
• Descriptor: HEAT SHOCK COGNATE 71 KDA PROTEIN, BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1, 5-methyl-1,5-dihydro-1,4,5,6,8-pentaazaacenaphthylen-3-amine, ... (6 entities in total)
• Functional Keywords: heat shock protein, hsp70, hsp72, hsc70, atpase, bag1, chaperone, fragment
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: P11142; Isoform 1: Nucleus. Isoform 2: Cytoplasm. Isoform 4: Cytoplasm: Q99933
• Total number of polymer chains: 2
• Total formula weight: 56829.53

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. (deposition date: 2015-09-22, release date: 2016-10-05, Last modification date: 2024-10-16)

Primary citation

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.
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

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

Experimental method

X-RAY DIFFRACTION (2 Å)