PDBsum entry 5aql

Chaperone

PDB id: 5aql

Contents

Protein chains

381 a.a.

113 a.a.

Ligands

TRS ×4

GOL ×5

Waters ×908

PDB id:

5aql

Name:

Chaperone

Title:

Fragment-based screening of hsp70 sheds light on the functional role of atp-binding site residues

Structure:

Heat shock cognate 71 kda protein. Chain: a, c. Fragment: nucleotide binding domain, residues 1-381. Synonym: heat shock 70 kda protein 8, lipopolysaccharide-associated protein 1, lap-1, lps-associated protein 1. Engineered: yes. Mutation: yes. Bag family molecular chaperone regulator 1. Chain: b, d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: ai.

Resolution:

1.69Å R-factor: 0.170 R-free: 0.197

Authors:

A.M.Jones,I.M.Westwood,J.D.Osborne,T.P.Matthews,M.D.Cheeseman, M.G.Rowlands,F.Jeganathan,R.Burke,D.Lee,N.Kadi,M.Liu,M.Richards, C.Mcandrew,N.Yahya,S.E.Dobson,K.Jones,P.Workman,I.Collins,R.L.M.Van Montfort

Key ref:

A.M.Jones et al. (2016). A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms. Sci Rep, 6, 34701. PubMed id: 27708405

Date:

22-Sep-15 Release date: 05-Oct-16

Protein chains

P11142  (HSP7C_HUMAN) -  Heat shock cognate 71 kDa protein from Homo sapiens

Seq: 646 a.a.

Struc: 381 a.a.*

Protein chains

Q99933  (BAG1_HUMAN) -  BAG family molecular chaperone regulator 1 from Homo sapiens

Seq: 345 a.a.

Struc: 113 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, C: E.C.3.6.4.10 - non-chaperonin molecular chaperone ATPase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Sci Rep 6:34701 (2016)

PubMed id: 27708405

A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.

A.M.Jones, I.M.Westwood, J.D.Osborne, T.P.Matthews, M.D.Cheeseman, M.G.Rowlands, F.Jeganathan, R.Burke, D.Lee, N.Kadi, M.Liu, M.Richards, C.McAndrew, N.Yahya, S.E.Dobson, K.Jones, P.Workman, I.Collins, R.L.van Montfort.

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.