Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases.

Proceedings of the National Academy of Sciences of the United States of America
Sheena McGowanJames C Whisstock

Abstract

Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the X-ray crystal structure of the monomeric PfA-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the X-ray crystal structure of the hexameric leucine aminopeptidase, PfA-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the PfA-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to PfA-M1, PfA-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate ...Continue Reading

References

Apr 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·D E GoldbergG B Henderson
Sep 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·S K BurleyW N Lipscomb
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Jul 2, 2003·Acta Crystallographica. Section D, Biological Crystallography·Elizabeth PottertonEleanor Dodson
Apr 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Puran S Sijwali, Philip J Rosenthal
Jan 1, 1993·Acta Crystallographica. Section D, Biological Crystallography·A T Brünger
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Liz PottertonMartin Noble
Jun 28, 2005·Nucleic Acids Research·Lukasz JaroszewskiAdam Godzik
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Andrew G W Leslie
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Philip Evans
May 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jun LiuDaniel E Goldberg
Jun 1, 2006·Proteins·Arun S KonagurthuArthur M Lesk
Nov 30, 2006·Biological Chemistry·Mikiko MatsuiLinda L Walling
Mar 1, 2007·Journal of Medicinal Chemistry·Marion FlipoRebecca F Deprez-Poulain
Sep 27, 2007·The Journal of Biological Chemistry·Seema Dalal, Michael Klemba
Dec 21, 2007·Acta Crystallographica. Section D, Biological Crystallography·Serge X CohenAnastassis Perrakis
May 28, 2008·Cellular Microbiology·Michael J Blackman
Jun 21, 2008·Acta Crystallographica. Section D, Biological Crystallography·Steve AndroulakisAshley M Buckle
Feb 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Sheena McGowanJohn P Dalton
May 26, 2009·Expert Opinion on Pharmacotherapy·Umberto D'Alessandro
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Michael Klemba
Oct 3, 2009·Trends in Biochemical Sciences·Tina S Skinner-AdamsJohn P Dalton

❮ Previous
Next ❯

Citations

Jul 26, 2011·Journal of Medicinal Chemistry·Artur MuchaŁukasz Berlicki
Aug 17, 2011·Proceedings of the National Academy of Sciences of the United States of America·Michael B HarbutDoron C Greenbaum
Apr 12, 2012·The Journal of Biological Chemistry·Melissa A ScrantonLinda L Walling
Mar 28, 2012·Antimicrobial Agents and Chemotherapy·Tina S Skinner-AdamsDonald L Gardiner
Mar 6, 2012·BMC Genomics·Timothy G LilburnYufeng Wang
Jan 8, 2011·Biological & Pharmaceutical Bulletin·Mahmoud Kandeel, Yukio Kitade
Jan 26, 2016·European Journal of Medicinal Chemistry·Nyssa DrinkwaterPeter J Scammells
Dec 1, 2015·Biochimie·Joyanta K ModakAnna Roujeinikova
Mar 31, 2010·Biochemical and Biophysical Research Communications·Manoj BhosaleDipankar Nandi
Jun 20, 2012·Journal of Molecular Biology·Komagal Kannan SivaramanSheena McGowan
Aug 21, 2013·Current Opinion in Structural Biology·Sheena McGowan
Jul 11, 2014·The Biochemical Journal·Nyssa Drinkwater, Sheena McGowan
May 12, 2010·Biochimie·Artur MuchaPaweł Kafarski
Jun 21, 2011·Biochimica Et Biophysica Acta·Hao LiMatthew Bogyo
Mar 14, 2012·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Arun Kumar SinghRajesh Singh
Jul 30, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Subhashree Rout, Rajani Kanta Mahapatra
Oct 25, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ifedayo Victor Ogungbe, William N Setzer
May 9, 2018·Parasite : Journal De La Société Française De Parasitologie·Sandie Escotte-BinetIsabelle Villena
Aug 8, 2017·Journal of Biomolecular Structure & Dynamics·Wei YangSheena McGowan
Nov 17, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Artur Mucha
Jun 11, 2014·Acta Crystallographica. Section D, Biological Crystallography·Kevin DuprezLi Fan
Jul 28, 2016·The Biochemical Journal·Nyssa DrinkwaterSheena McGowan
Mar 21, 2019·Frontiers in Microbiology·Manasi MishraShailja Singh
Aug 31, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Joyanta K Modak, Anna Roujeinikova
Dec 12, 2020·The Journal of Biological Chemistry·Tess R MalcolmSheena McGowan
Jun 17, 2021·The Biochemical Journal·Tess R MalcolmSheena McGowan
Dec 13, 2018·Journal of Medicinal Chemistry·Natalie B VinhSheena McGowan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.