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Experimental Technique/Method:X-RAY DIFFRACTION Resolution:1.9 Classification:TRANSFERASE Release Date:2018-02-28 Deposition Date:2017-09-05 Revision Date: Molecular Weight:98387.05 Macromolecule Type:Protein Residue Count:843 Atom Site Count:6656 DOI:10.2210/pdb5ox0/pdb Abstract: Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the β-pocket by studying the inhibitory effect of six different groups at the para position of 3-(β-d-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a K
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:2.12 Classification:TRANSFERASE Release Date:2018-02-28 Deposition Date:2017-02-11 Revision Date: Molecular Weight:37591.37 Macromolecule Type:Protein Residue Count:327 Atom Site Count:2237 DOI:10.2210/pdb5n51/pdb
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:2.57 Classification:TRANSFERASE Release Date:2018-02-28 Deposition Date:2017-02-23 Revision Date: Molecular Weight:182331.36 Macromolecule Type:Protein Residue Count:1608 Atom Site Count:12735 DOI:10.2210/pdb5x71/pdb
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:1.95 Classification:HYDROLASE Release Date:2018-02-28 Deposition Date:2018-01-29 Revision Date: Molecular Weight:155497.56 Macromolecule Type:Protein Residue Count:1332 Atom Site Count:10884 DOI:10.2210/pdb6ca1/pdb
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:2.3 Classification:HYDROLASE, LYASE/DNA Release Date:2018-02-28 Deposition Date:2017-07-31 Revision Date: Molecular Weight:74964.62 Macromolecule Type:Protein#DNA Residue Count:593 Atom Site Count:5193 DOI:10.2210/pdb5wn1/pdb Abstract: Human apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is an essential DNA repair enzyme which uses a single active site to process DNA damage via two distinct activities: (1) AP-endonuclease and (2) 3' to 5' exonuclease. The AP-endonuclease activity cleaves at AP-sites, while the exonuclease activity excises bulkier 3' mismatches and DNA damage to generate clean DNA ends suitable for downstream repair. Molecular details of the exonuclease reaction and how one active site can accommodate various toxic DNA repair intermediates remains elusive despite being biologically important. Here, we report multiple high-resolution APE1-DNA structural snapshots revealing how APE1 removes 3' mismatches and DNA damage by placing the 3' group within the intra-helical DNA cavity via a non-base flipping mechanism. This process is facilitated by a DNA nick, instability of a mismatched/damaged base, and bending of the DNA. These results illustrate how APE1 cleanses DNA dirty-ends to generate suitable substrates for downstream repair enzymes.
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  • Tabular Data
Experimental Technique/Method:NEUTRON DIFFRACTION Resolution:1.49 Classification:HYDROLASE Release Date:2018-02-28 Deposition Date:2016-12-13 Revision Date: Molecular Weight:23472.53 Macromolecule Type:Protein Residue Count:223 Atom Site Count:1599 DOI:10.2210/pdb5mo1/pdb
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:3.26 Classification:TRANSFERASE Release Date:2018-02-28 Deposition Date:2017-02-20 Revision Date: Molecular Weight:330580.22 Macromolecule Type:Protein Residue Count:2880 Atom Site Count:20503 DOI:10.2210/pdb5uw1/pdb
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:1.85 Classification:TRANSFERASE Release Date:2018-02-28 Deposition Date:2017-09-05 Revision Date: Molecular Weight:98085.0 Macromolecule Type:Protein Residue Count:843 Atom Site Count:6638 DOI:10.2210/pdb5ox1/pdb Abstract: Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the β-pocket by studying the inhibitory effect of six different groups at the para position of 3-(β-d-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a K
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:1.5 Classification:LYASE Release Date:2018-02-28 Deposition Date:2017-02-21 Revision Date: Molecular Weight:106872.6 Macromolecule Type:Protein Residue Count:948 Atom Site Count:6375 DOI:10.2210/pdb5ux1/pdb
Data Types:
  • Tabular Data
Experimental Technique/Method:X-RAY DIFFRACTION Resolution:2.1 Classification:OXIDOREDUCTASE Release Date:2018-02-28 Deposition Date:2017-05-19 Revision Date: Molecular Weight:126579.48 Macromolecule Type:Protein Residue Count:1156 Atom Site Count:8620 DOI:10.2210/pdb5o22/pdb Abstract: The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target.
Data Types:
  • Tabular Data
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