The crystal structure of carnitine palmitoyltransferase 2 and implications for diabetes treatment

Structure
Arne C RuferMichael Hennig

Abstract

Carnitine palmitoyltransferases 1 and 2 (CPTs) facilitate the import of long-chain fatty acids into mitochondria. Modulation of the catalytic activity of the CPT system is currently under investigation for the development of novel drugs against diabetes mellitus. We report here the 1.6 A resolution structure of the full-length mitochondrial membrane protein CPT-2. The structure of CPT-2 in complex with the generic CPT inhibitor ST1326 ([R]-N-[tetradecylcarbamoyl]-aminocarnitine), a substrate analog mimicking palmitoylcarnitine and currently in clinical trials for diabetes mellitus treatment, was solved at 2.5 A resolution. These structures of CPT-2 provide insight into the function of residues involved in substrate binding and determination of substrate specificity, thereby facilitating the rational design of antidiabetic drugs. We identify a sequence insertion found in CPT-2 that mediates membrane localization. Mapping of mutations described for CPT-2 deficiency, a hereditary disorder of lipid metabolism, implies effects on substrate recognition and structural integrity of CPT-2.

References

Aug 1, 1992·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·M BarnettK O'Dea
Mar 1, 1992·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·A HübingerF A Gries
Apr 28, 1968·Journal of Molecular Biology·B W Matthews
Jan 1, 1984·Preparative Biochemistry·D Rickwood, A Hayes
Aug 1, 1995·Diabetes Research and Clinical Practice·A Kashiwagi
Feb 15, 1997·European Journal of Biochemistry·J D McGarry, N F Brown
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
May 20, 1999·Nature Structural Biology·A PerrakisV S Lamzin
Dec 23, 1999·Molecular Genetics and Metabolism·J P BonnefontL Thuillier
Sep 22, 2000·Acta Crystallographica. Section D, Biological Crystallography·P RoversiG Bricogne
Mar 21, 2001·Biochimica Et Biophysica Acta·R R RamsayF R van der Leij
Apr 3, 2001·Current Pharmaceutical Design·A S Wagman, J M Nuss
Jun 8, 2002·Current Pharmaceutical Design·Gregory R Bebernitz, Herbert F Schuster
Jan 30, 2003·Acta Crystallographica. Section D, Biological Crystallography·Allan D'ArcyAlexander Haber
Feb 4, 2003·The Journal of Biological Chemistry·Donghai WuRobert McKenna
Dec 4, 2003·Biochemical Society Transactions·K N Frayn
Apr 22, 2004·Journal of Structural Biology·Lakshmanan GovindasamyDonghai Wu
May 25, 2004·The Journal of Biological Chemistry·Yu-Shan HsiaoLiang Tong
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Sep 15, 2004·Molecular Aspects of Medicine·Jean-Paul BonnefontJean Bastin
Sep 15, 2004·Molecular Aspects of Medicine·M E Rubio-GozalboR J A Wanders
Oct 20, 2004·The Journal of Biological Chemistry·Gerwald JoglLiang Tong
Nov 3, 2004·Biochimica Et Biophysica Acta·Hildur Palsdottir, Carola Hunte
Dec 14, 2004·International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity·A G DullooG Solinas
May 10, 2005·Physiology & Behavior·Gabriele V RonnettYajun Tu

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Citations

Nov 2, 2014·The Pediatric Infectious Disease Journal·Jianxia HuPeipei Liu
Jul 28, 2006·The Journal of Biological Chemistry·Yu-Shan HsiaoLiang Tong
Jul 3, 2007·BMC Structural Biology·Andrei L LomizeHenry I Mosberg
Jul 30, 2010·Quarterly Reviews of Biophysics·Kutti R Vinothkumar, Richard Henderson
May 12, 2009·Cellular and Molecular Life Sciences : CMLS·Arne C RuferMichael Hennig
Sep 5, 2008·Current Opinion in Neurology·Claudio Bruno, Salvatore Dimauro
Jun 14, 2008·Molecular Genetics and Metabolism·Paul J IsacksonGeorgirene D Vladutiu
Oct 21, 2015·Biochimica Et Biophysica Acta·Leila MotlaghStephan Zierz
Sep 26, 2006·Molecular Genetics and Metabolism·Paul J IsacksonGeorgirene D Vladutiu
Jun 20, 2006·Biochemical and Biophysical Research Communications·Yu-Shan HsiaoLiang Tong
Mar 8, 2014·Journal of the Neurological Sciences·Diana Lehmann, Stephan Zierz
Apr 18, 2006·Structure·Andrea Mattevi
Apr 29, 2016·Neurology. Genetics·Leila MotlaghStephan Zierz
Apr 21, 2011·Journal of Medicinal Chemistry·Simona M CeccarelliArduino Arduini
Sep 1, 2016·Nucleic Acids Research·Dariusz RatmanKarolien De Bosscher
Jan 6, 2017·International Journal of Molecular Sciences·Diana LehmannStephan Zierz
Apr 25, 2007·The Journal of Biological Chemistry·Eduardo López-ViñasPaulino Gómez-Puertas
Jul 26, 2007·The Journal of Biological Chemistry·Audrey FayeCarina Prip-Buus
Feb 2, 2019·Mini Reviews in Medicinal Chemistry·Khairul Anwar ZarkasiZakiah Jubri
May 3, 2018·ACS Infectious Diseases·Rahul TyagiMakedonka Mitreva

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