6H54
CRYSTAL STRUCTURE OF BOVINE HSC70(AA1-554)E213A/D214A IN COMPLEX WITH INHIBITOR VER155008
Summary for 6H54
| Entry DOI | 10.2210/pdb6h54/pdb |
| Related | 4fl9 |
| Descriptor | Heat shock cognate 71 kDa protein, trimethylamine oxide, 4-[[(2R,3S,4R,5R)-5-[6-amino-8-[(3,4-dichlorophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-oxolan-2-yl]methoxymethyl]benzonitrile, ... (6 entities in total) |
| Functional Keywords | chaperone, hsc70, vernalis inhibitor |
| Biological source | Bos taurus (cattle) |
| Total number of polymer chains | 1 |
| Total formula weight | 61940.78 |
| Authors | Plank, C.,Zehe, M.,Grimm, C.,Sotriffer, C. (deposition date: 2018-07-23, release date: 2019-08-14, Last modification date: 2024-02-14) |
| Primary citation | Zehe, M.,Kehrein, J.,Schollmayer, C.,Plank, C.,Kovacs, H.,Merino Asumendi, E.,Holzgrabe, U.,Grimm, C.,Sotriffer, C. Combined In-Solution Fragment Screening and Crystallographic Binding-Mode Analysis with a Two-Domain Hsp70 Construct. Acs Chem.Biol., 2024 Cited by PubMed Abstract: Heat shock protein 70 (Hsp70) isoforms are key players in the regulation of protein homeostasis and cell death pathways and are therefore attractive targets in cancer research. Developing nucleotide-competitive inhibitors or allosteric modulators, however, has turned out to be very challenging for this protein family, and no Hsp70-directed therapeutics have so far become available. As the field could profit from alternative starting points for inhibitor development, we present the results of a fragment-based screening approach on a two-domain Hsp70 construct using in-solution NMR methods, together with X-ray-crystallographic investigations and mixed-solvent molecular dynamics simulations. The screening protocol resulted in hits on both domains. In particular, fragment binding in a deeply buried pocket at the substrate-binding domain could be detected. The corresponding site is known to be important for communication between the nucleotide-binding and substrate-binding domains of Hsp70 proteins. The main fragment identified at this position also offers an interesting starting point for the development of a dual Hsp70/Hsp90 inhibitor. PubMed: 38317495DOI: 10.1021/acschembio.3c00589 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.02 Å) |
Structure validation
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