5AQS: Fragment-based Screening Of Hsp70 Sheds Light On The Functional Role Of Atp-binding Site Residues

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.
PDB ID: 5AQSDownload
MMDB ID: 143656
PDB Deposition Date: 2015/9/22
Updated in MMDB: 2016/10
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 5AQS: dimeric; determined by author and by software (PISA)
Molecular Components in 5AQS
Label Count Molecule
Proteins (3 molecules)
Heat Shock Cognate 71 KDA Protein(Gene symbol: HSPA8)
Molecule annotation
BAG Family Molecular Chaperone Regulator 1(Gene symbol: BAG1)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB