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MitoNEET: A New Approach for Designing Diabetes Drugs

Technology Benefits

The overall structure is described as a beta rich domain with a strand swap from opposite ends of the primary structure that forms a ‘beta cap’ domain. Crystallographic analysis was performed on isolated and truncated mitoNEET protein (AA33-108) to determine the precise structure of the novel fold. The Fe-S clusters are 16A from each other, oriented close to the outer mitochondrial membrane. Pioglitzaone, a member of the thiazolidinedione class of insulin-sensitizing drugs has always been thought to work thru the nuclear receptor PPAR-gamma by effecting lipid metabolism and oxidative capacity. Investigators at UC San Diego have demonstrated that it also binds to the 2FE-2S binding site of mitoNEET.

Detailed Technology Description

The overall structure is described as a beta rich domain with a strand swap from opposite ends of the primary structure that forms a ‘beta cap’ domain. Crystallographic analysis was performed on isolated and truncated mitoNEET protein (AA33-108) to determine the precise structure of the novel fold. The Fe-S clusters are 16A from each other, oriented close to the outer mitochondrial membrane. Pioglitzaone, a member of the thiazolidinedione class of insulin-sensitizing drugs has always been thought to work thru the nuclear receptor PPAR-gamma by effecting lipid metabolism and oxidative capacity. Investigators at UC San Diego have demonstrated that it also binds to the 2FE-2S binding site of mitoNEET.

Supplementary Information

Patent Number: US8350007B2
Application Number: US2010673469A
Inventor: Jennings, Patricia A | Dixon, Jack | Nechushtai, Rachel
Priority Date: 17 Aug 2007
Priority Number: US8350007B2
Application Date: 21 Jul 2011
Publication Date: 8 Jan 2013
IPC Current: C07K000100
US Class: 530350
Assignee Applicant: The Regents of the University of California
Title: Crystal structure of human mitoNEET protein
Usefulness: Crystal structure of human mitoNEET protein
Summary: As human mitochondrial membrane protein crystal for identifying a compound for the treatment of a mitoNEET-associated disorder selected from type II diabetes, insulin resistance, multiple sclerosis, Alzheimer's disease or amyotrophic lateral sclerosis (claimed), Syndrome X, hyperinsulemia, obesity, dyslipidemia, heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa, cardiovascular diseases and conditions including hypertension, atherosclerosis, arteriosclerosis and hypertriglyceridemia.
Novelty: New crystal comprising a human mitochondrial membrane protein having specific amino acid sequence, useful for identifying a compound for treating e.g. type II diabetes, insulin resistance, multiple sclerosis, Alzheimer's disease, obesity

Industry

Chemical/Material

Sub Category

Chemical/Material Application

Application No.

8350007

Others

Related Materials

Tech ID/UC Case

19440/2008-040-0

Related Cases

2008-040-0

*Abstract

MitoNEET is an outer mitochondrial membrane protein that binds pioglitzaone (ActosTM), an insulin-sensitizing drug of the thiazolidinedione class used in the treatment of Type II diabetes. This protein has a unique dimeric structure where the two components interact to form a new fold not previously seen in any Fe-S protein structures or in any know protein. This new fold forms a binding domain between two acid labile 2Fe-2S clusters.

Defects in the ability of the mitoNEET protein to control assembly and transfer of Fe-S clusters typically result in mitochondrial dysfunction such as that found in Type II diabetes.

*IP Issue Date

Jan 8, 2013

*Principal Investigator

Name: Jack Dixon

Department:

Name: Patricia Jennings

Department:

Name: Rachel Nechushtai

Department:

Name: Rachel Nechushtai

Department:

Country/Region

USA