Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations

Biochemistry
B S SelinskyP J Loll

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) block prostanoid biosynthesis by inhibiting prostaglandin H(2) synthase (EC 1.14.99.1). NSAIDs are either rapidly reversible competitive inhibitors or slow tight-binding inhibitors of this enzyme. These different modes of inhibition correlate with clinically important differences in isoform selectivity. Hypotheses have been advanced to explain the different inhibition kinetics, but no structural data have been available to test them. We present here crystal structures of prostaglandin H(2) synthase-1 in complex with the inhibitors ibuprofen, methyl flurbiprofen, flurbiprofen, and alclofenac at resolutions ranging from 2.6 to 2.75 A. These structures allow direct comparison of enzyme complexes with reversible competitive inhibitors (ibuprofen and methyl flurbiprofen) and slow tight-binding inhibitors (alclofenac and flurbiprofen). The four inhibitors bind to the same site and adopt similar conformations. In all four complexes, the enzyme structure is essentially unchanged, exhibiting only minimal differences in the inhibitor binding site. These results argue strongly against hypotheses that explain the difference between slow tight-binding and fast reversible competitive inhibition by...Continue Reading

References

Jun 6, 1994·FEBS Letters·D Picot, R M Garavito
Oct 16, 1999·Bioorganic & Medicinal Chemistry Letters·O LlorensD Mauleon
Aug 31, 2000·Annual Review of Biochemistry·W L SmithR M Garavito

❮ Previous
Next ❯

Citations

Jul 16, 2009·Journal of Molecular Modeling·Caitlin E Cassidy, William N Setzer
Mar 20, 2010·Journal of Molecular Modeling·Souhila Bouaziz-TerrachetSafia Taïri-Kellou
Aug 2, 2005·Journal of Computer-aided Molecular Design·Hwangseo Park, Sangyoub Lee
Dec 14, 2011·Journal of Computer-aided Molecular Design·Robert D Clark, Marvin Waldman
Jan 27, 2004·Bioorganic & Medicinal Chemistry Letters·Kushol GuptaPatrick J Loll
Feb 28, 2004·European Journal of Medicinal Chemistry·Miljen MartićSanja Kostrun
Dec 5, 2002·Archives of Biochemistry and Biophysics·G Phillip HochgesangLawrence J Marnett
Nov 16, 2002·Prostaglandins & Other Lipid Mediators·R Michael GaravitoDavid L DeWitt
Nov 16, 2002·Prostaglandins & Other Lipid Mediators·Lawrence J Marnett
Jun 20, 2003·Progress in Lipid Research·Richard J KulmaczAh-Lim Tsai
Dec 26, 2001·Current Opinion in Structural Biology·R G KurumbailL J Marnett
Mar 12, 2002·Journal of Molecular Graphics & Modelling·Oriol LlorensDavid Mauleon
May 3, 2011·Journal of Chemical Information and Modeling·Muhammad K HaiderRoderick E Hubbard
Dec 8, 2011·Journal of Chemical Information and Modeling·David R HallSandor Vajda
Mar 1, 2012·Journal of Chemical Information and Modeling·Vojtěch SpiwokBlanka Králová
Sep 29, 2011·Chemical Reviews·William L SmithPer-Johan Jakobsson
Nov 19, 2011·Journal of Medicinal Chemistry·Aldino ViegasEurico J Cabrita
Jul 19, 2008·Nature Reviews. Drug Discovery·Yusuf Tanrikulu, Gisbert Schneider
Mar 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Vittorio LimongelliMichele Parrinello
Apr 5, 2013·Proceedings of the National Academy of Sciences of the United States of America·Vittorio LimongelliMichele Parrinello
Sep 3, 2010·The Journal of Biological Chemistry·Kelsey C DugganLawrence J Marnett
Apr 22, 2004·The Journal of Biological Chemistry·Wen LiuRichard J Kulmacz
Feb 20, 2008·Journal of Biomolecular Structure & Dynamics·V RajakrishnanGita Subba Rao
Jan 28, 2009·Acta Crystallographica. Section D, Biological Crystallography·Thomas Lütteke
Jan 20, 2010·Journal of Postgraduate Medicine·R Vijayakrishnan
Nov 26, 2013·Bioorganic Chemistry·Cevher Gundogdu-HizliatesLevent Cavas
Feb 8, 2014·Archives of Biochemistry and Biophysics·Benjamin J OrlandoMichael G Malkowski
Jul 30, 2004·Proceedings of the National Academy of Sciences of the United States of America·Riccardo BertiniFrancesco Colotta
Sep 21, 2011·Nature Chemical Biology
Oct 23, 2013·Organic & Biomolecular Chemistry·Ole TietzFrank Wuest
Jul 2, 2011·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Naoko ItoYasuhiko Yamada
Nov 25, 2011·Expert Review of Clinical Pharmacology·Kathleen M KnightsJohn O Miners
Jul 14, 2007·Journal of Pharmaceutical Sciences·M L VuebaL A E Batista de Carvalho
Jan 18, 2016·European Journal of Medicinal Chemistry·Marco MiglioreRita Scarpelli
May 11, 2013·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·Igor NovakSean P McGlynn

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.