Structural Basis for AMPK Activation: Natural and Synthetic Ligands Regulate Kinase Activity from Opposite Poles by Different Molecular Mechanisms

被引：140

作者：

Calabrese, Matthew F. ^{[1
]}

Rajamohan, Francis ^{[1
]}

Harris, Melissa S. ^{[1
]}

Caspers, Nicole L. ^{[1
]}

Magyar, Rachelle ^{[1
]}

Withka, Jane M. ^{[1
]}

Wang, Hong ^{[1
]}

Borzilleri, Kris A. ^{[1
]}

Sahasrabudhe, Parag V. ^{[1
]}

Hoth, Lise R. ^{[1
]}

Geoghegan, Kieran F. ^{[1
]}

Han, Seungil ^{[1
]}

Brown, Janice ^{[1
]}

Subashi, Timothy A. ^{[1
]}

Reyes, Allan R. ^{[2
]}

Frisbie, Richard K. ^{[1
]}

Ward, Jessica ^{[2
]}

Miller, Russell A. ^{[2
]}

Landro, James A. ^{[2
]}

Londregan, Allyn T. ^{[1
]}

Carpino, Philip A. ^{[2
]}

Cabral, Shawn ^{[1
]}

Smith, Aaron C. ^{[1
]}

Conn, Edward L. ^{[1
]}

Cameron, Kimberly O. ^{[2
]}

Qiu, Xiayang ^{[1
]}

Kurumbail, Ravi G. ^{[1
]}

机构：

[1] Pfizer Inc, Worldwide Res & Dev, Groton, CT 06340 USA

[2] Pfizer Inc, Worldwide Res & Dev, Cambridge, MA 02139 USA

来源：

STRUCTURE | 2014年 / 22卷 / 08期

关键词：

DEPENDENT PROTEIN-KINASE; UPSTREAM KINASE; POSTTRANSLATIONAL MODIFICATIONS; IDENTIFICATION; A-769662; SUBUNIT; BETA; PURIFICATION; RECOGNITION; SENSOR;

D O I：

10.1016/j.str.2014.06.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 alpha 2 beta 1 gamma 1 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 alpha 2 beta 1 gamma 1 structure and provide insight into the distinct molecular mechanisms of AMPK regulation by AMP and A769662.

引用

页码：1161 / 1172

页数：12

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