title: Structural basis for AMPK activation: natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms.
abstract: AMP-activated protein kinase (AMPK) is a principal metabolic regulator affecting growth and response to cellular stress. Comprised of catalytic and regulatory subunits, each present in multiple forms, AMPK is best described as a family of related enzymes. In recent years, AMPK has emerged as a desirable target for modulation of numerous diseases, yet clinical therapies remain elusive. Challenges result, in part, from an incomplete understanding of the structure and function of full-length heterotrimeric complexes. In this work, we provide the full-length structure of the widely expressed α1β1γ1 isoform of mammalian AMPK, along with detailed kinetic and biophysical characterization. We characterize binding of the broadly studied synthetic activator A769662 and its analogs. Our studies follow on the heels of the recent disclosure of the α2β1γ1 structure and provide insight into the distinct molecular mechanisms of AMPK regulation by AMP and A769662.
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Matthew F
authors: MF
authors: Calabrese
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Francis
authors: F
authors: Rajamohan
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Melissa S
authors: MS
authors: Harris
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Nicole L
authors: NL
authors: Caspers
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Rachelle
authors: R
authors: Magyar
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Jane M
authors: JM
authors: Withka
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Hong
authors: H
authors: Wang
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Kris A
authors: KA
authors: Borzilleri
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Parag V
authors: PV
authors: Sahasrabudhe
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Lise R
authors: LR
authors: Hoth
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Kieran F
authors: KF
authors: Geoghegan
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Seungil
authors: S
authors: Han
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Janice
authors: J
authors: Brown
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Timothy A
authors: TA
authors: Subashi
authors: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors: Allan R
authors: AR
authors: Reyes
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Richard K
authors: RK
authors: Frisbie
authors: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors: Jessica
authors: J
authors: Ward
authors: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors: Russell A
authors: RA
authors: Miller
authors: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors: James A
authors: JA
authors: Landro
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Allyn T
authors: AT
authors: Londregan
authors: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors: Philip A
authors: PA
authors: Carpino
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Shawn
authors: S
authors: Cabral
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Aaron C
authors: AC
authors: Smith
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Edward L
authors: EL
authors: Conn
authors: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors: Kimberly O
authors: KO
authors: Cameron
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors: Xiayang
authors: X
authors: Qiu
authors: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA. Electronic address: ravi.g.kurumbail@pfizer.com.
authors: Ravi G
authors: RG
authors: Kurumbail
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000495:Allosteric Site / Q000235:genetics; D001713:Biphenyl Compounds; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D011753:Pyrones / Q000378:metabolism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013876:Thiophenes / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D008024:Ligands; D020033:Protein Isoforms; D011753:Pyrones; D013876:Thiophenes; D000249:Adenosine Monophosphate; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile