7gyx

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Crystal Structure of HSP72 in complex with ligand 11 at 21.45 MGy X-ray dose

Structural highlights

7gyx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.15Å
Ligands:1PS, A1ACZ, DMS, EDO, PEG, PO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HS71A_HUMAN In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).[1] [2] [3]

Publication Abstract from PubMed

Protein-inhibitor crystal structures aid medicinal chemists in efficiently improving the potency and selectivity of small-molecule inhibitors. It is estimated that a quarter of lead molecules in drug discovery projects are halogenated. Protein-inhibitor crystal structures have shed light on the role of halogen atoms in ligand binding. They form halogen bonds with protein atoms and improve shape complementarity of inhibitors with protein binding sites. However, specific radiation damage (SRD) can cause cleavage of carbon-halogen (C-X) bonds during X-ray diffraction data collection. This study shows significant C-X bond cleavage in protein-ligand structures of the therapeutic cancer targets B-cell lymphoma 6 (BCL6) and heat shock protein 72 (HSP72) complexed with halogenated ligands, which is dependent on the type of halogen and chemical structure of the ligand. The study found that metrics used to evaluate the fit of the ligand to the electron density deteriorated with increasing X-ray dose, and that SRD eliminated the anomalous signal from brominated ligands. A point of diminishing returns is identified, where collecting highly redundant data reduces the anomalous signal that may be used to identify binding sites of low-affinity ligands or for experimental phasing. Straightforward steps are proposed to mitigate the effects of C-X bond cleavage on structures of proteins bound to halogenated ligands and to improve the success of anomalous scattering experiments.

Specific radiation damage to halogenated inhibitors and ligands in protein-ligand crystal structures.,Rodrigues MJ, Cabry M, Collie G, Carter M, McAndrew C, Owen RL, Bellenie BR, Le Bihan YV, van Montfort RLM J Appl Crystallogr. 2024 Nov 26;57(Pt 6):1951-1965. doi: , 10.1107/S1600576724010549. eCollection 2024 Dec 1. PMID:39628887[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. Perez-Vargas J, Romero P, Lopez S, Arias CF. The peptide-binding and ATPase domains of recombinant hsc70 are required to interact with rotavirus and reduce its infectivity. J Virol. 2006 Apr;80(7):3322-31. PMID:16537599 doi:http://dx.doi.org/80/7/3322
  2. Liu X, Liu D, Qian D, Dai J, An Y, Jiang S, Stanley B, Yang J, Wang B, Liu X, Liu DX. Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. J Biol Chem. 2012 Jun 1;287(23):19599-609. doi: 10.1074/jbc.M112.363622. Epub, 2012 Apr 23. PMID:22528486 doi:http://dx.doi.org/10.1074/jbc.M112.363622
  3. Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park BV, Pan Z, Zhang J, Dang E, Li Z, Wang H, Luo W, Li L, Semenza GL, Zheng SG, Loser K, Tsun A, Greene MI, Pardoll DM, Pan F, Li B. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity. 2013 Aug 22;39(2):272-85. doi: 10.1016/j.immuni.2013.08.006. PMID:23973223 doi:http://dx.doi.org/10.1016/j.immuni.2013.08.006
  4. Rodrigues MJ, Cabry M, Collie G, Carter M, McAndrew C, Owen RL, Bellenie BR, Le Bihan YV, van Montfort RLM. Specific radiation damage to halogenated inhibitors and ligands in protein-ligand crystal structures. J Appl Crystallogr. 2024 Nov 26;57(Pt 6):1951-1965. PMID:39628887 doi:10.1107/S1600576724010549

Contents


PDB ID 7gyx

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