6E4W
Structure of AMPK bound to activator
Summary for 6E4W
| Entry DOI | 10.2210/pdb6e4w/pdb |
| Descriptor | 5'-AMP-activated protein kinase catalytic subunit alpha-1, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (9 entities in total) |
| Functional Keywords | kinase, ampk, activator, allostery, transferase-activator complex, transferase |
| Biological source | Rattus norvegicus (Rat) More |
| Total number of polymer chains | 3 |
| Total formula weight | 120634.54 |
| Authors | Calabrese, M.F.,Kurumbail, R.G. (deposition date: 2018-07-18, release date: 2018-08-08, Last modification date: 2024-10-23) |
| Primary citation | Ryder, T.F.,Calabrese, M.F.,Walker, G.S.,Cameron, K.O.,Reyes, A.R.,Borzilleri, K.A.,Delmore, J.,Miller, R.,Kurumbail, R.G.,Ward, J.,Kung, D.W.,Brown, J.A.,Edmonds, D.J.,Eng, H.,Wolford, A.C.,Kalgutkar, A.S. Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK). J. Med. Chem., 61:7273-7288, 2018 Cited by PubMed Abstract: Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1-3 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1-3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1-3 and M1-M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates. PubMed: 30036059DOI: 10.1021/acs.jmedchem.8b00807 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.35 Å) |
Structure validation
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