Crystal Structure of AMP Activated Protein Kinase Regulatory Complex with AMP or ATP
Lead Inventors: Lawrence ShapiroProblem or Unmet Need:The drug development of energy balance disorders, such as obesity and type-2 diabetes, is limited by lack of detailed understanding of metabolic control. A key target in this area is the adenosine monophosphate-activated protein kinase (AMPK) complex. AMPK is a master regulator of cellular energy balance. For example, its activity on up-regulating import of glucose into a cell is an important consideration for treating diabetes. However, there were only AMPK crystal structures in isolation from the regulatory subunits. The lack of three dimensional structures of the regulatory subunits has hindered the development of useful reagents. In particular, complexes comprising an AMPK regulatory region and an AMPK ligand, will play a critical role in rational based small compound design for diagnosis, prevention or treatment. Details of the Invention In this invention, researchers led by Professor Lawrence Shapiro at Columbia University presents hetero-trimeric protein crystal structures of the regulatory domains of AMP activated protein kinase bound with either AMP or ATP. The high resolution three dimensional structures will be the basis for designing compounds which turn on and off the catalytic activity of AMPK. These crystal structures also show the arraignment of the regulatory subunits and the metabolites that govern the enzyme behavior.
These structures are of the regulatory domains of AMPK, which was not available previously These structures provide three dimensional structures with crucial atomic level details which was not available previously, and is essential basis for drug design These structures reveal a detailed mechanism of activating and inhibitory effects of the metabolites on the enzymatics activity of AMPK These crystal structures show the difference between the inactive and the active forms of the energy sensing subunits so they can be used to design compounds that mimic both statesOpportunities Sponsored research funding of continued research Licensing
These structures will be basis for identifying, designing, selecting and testing small molecules, including both agonists and antagonists, of the AMP kinase Can be used to design small molecules that mimic either the active state or the inactive state These compounds can be used as prevention or treatment of diabetes and/or obesity These compounds may be used to provide symptom relief for diabetes These compounds can be used as tools for clinical research These structures may be used to design compounds for modifying other physiological events mediated by AMP kinase
Details of the Invention In this invention, researchers led by Professor Lawrence Shapiro at Columbia University presents hetero-trimeric protein crystal structures of the regulatory domains of AMP activated protein kinase bound with either AMP...
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