Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non‐diphosphate Inhibitors
Abstract
Abstract Isoprenoid biosynthesis is an important area for anti‐infective drug development. One isoprenoid target is ( E )‐1‐hydroxy‐2‐methyl‐but‐2‐enyl 4‐diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H + /2e − reduction. IspH contains a 4 Fe−4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe−4 S clusters by η 1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) binding. Based on these ideas, we used in silico methods to find drug‐like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a K i value of ≈500 n m against Pseudomonas aeruginosa IspH.
- Authors:
-
- Department of Chemistry University of Illinois 600 South Mathews Avenue Urbana IL 61801 USA
- Department of Chemistry and Biochemistry University of California at San Diego La Jolla CA 92093 USA
- Department of Chemistry University of California 1 Shields Avenue Davis CA 95616 USA, Lawrence Berkeley National Laboratory 1 Cyclotron Road Berkeley CA 94720 USA
- Center for Biophysics and Computational Biology 607 South Mathews Avenue Urbana IL 61801 USA
- Department of Chemistry and Biochemistry University of California at San Diego La Jolla CA 92093 USA, Howard Hughes Medical Institute University of California at San Diego La Jolla CA 92093 USA, National Biomedical Computation Resource University of California at San Diego La Jolla CA 92093 USA
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1401763
- Grant/Contract Number:
- 39192/43032; 2015B1134
- Resource Type:
- Publisher's Accepted Manuscript
- Journal Name:
- ChemBioChem: a European journal of chemical biology
- Additional Journal Information:
- Journal Name: ChemBioChem: a European journal of chemical biology Journal Volume: 18 Journal Issue: 10; Journal ID: ISSN 1439-4227
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- France
- Language:
- English
Citation Formats
O'Dowd, Bing, Williams, Sarah, Wang, Hongxin, No, Joo Hwan, Rao, Guodong, Wang, Weixue, McCammon, J. Andrew, Cramer, Stephen P., and Oldfield, Eric. Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non‐diphosphate Inhibitors. France: N. p., 2017.
Web. doi:10.1002/cbic.201700052.
O'Dowd, Bing, Williams, Sarah, Wang, Hongxin, No, Joo Hwan, Rao, Guodong, Wang, Weixue, McCammon, J. Andrew, Cramer, Stephen P., & Oldfield, Eric. Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non‐diphosphate Inhibitors. France. https://doi.org/10.1002/cbic.201700052
O'Dowd, Bing, Williams, Sarah, Wang, Hongxin, No, Joo Hwan, Rao, Guodong, Wang, Weixue, McCammon, J. Andrew, Cramer, Stephen P., and Oldfield, Eric. Fri .
"Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non‐diphosphate Inhibitors". France. https://doi.org/10.1002/cbic.201700052.
@article{osti_1401763,
title = {Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non‐diphosphate Inhibitors},
author = {O'Dowd, Bing and Williams, Sarah and Wang, Hongxin and No, Joo Hwan and Rao, Guodong and Wang, Weixue and McCammon, J. Andrew and Cramer, Stephen P. and Oldfield, Eric},
abstractNote = {Abstract Isoprenoid biosynthesis is an important area for anti‐infective drug development. One isoprenoid target is ( E )‐1‐hydroxy‐2‐methyl‐but‐2‐enyl 4‐diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H + /2e − reduction. IspH contains a 4 Fe−4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe−4 S clusters by η 1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) binding. Based on these ideas, we used in silico methods to find drug‐like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a K i value of ≈500 n m against Pseudomonas aeruginosa IspH.},
doi = {10.1002/cbic.201700052},
journal = {ChemBioChem: a European journal of chemical biology},
number = 10,
volume = 18,
place = {France},
year = {Fri Apr 07 00:00:00 EDT 2017},
month = {Fri Apr 07 00:00:00 EDT 2017}
}
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Works referenced in this record:
Isoprenoid Biosynthesis via the MEP Pathway: In Vivo Mössbauer Spectroscopy Identifies a [4Fe-4S] 2+ Center with Unusual Coordination Sphere in the LytB Protein
journal, September 2009
- Seemann, Myriam; Janthawornpong, Karnjapan; Schweizer, Julia
- Journal of the American Chemical Society, Vol. 131, Issue 37
Observation of the FeCN and FeCO Vibrations in the Active Site of [NiFe] Hydrogenase by Nuclear Resonance Vibrational Spectroscopy
journal, November 2012
- Kamali, Saeed; Wang, Hongxin; Mitra, Devrani
- Angewandte Chemie International Edition, Vol. 52, Issue 2
Inhibition of the Fe 4 S 4 -Cluster-Containing Protein IspH (LytB): Electron Paramagnetic Resonance, Metallacycles, and Mechanisms
journal, May 2010
- Wang, Ke; Wang, Weixue; No, Joo-Hwan
- Journal of the American Chemical Society, Vol. 132, Issue 19
Isoprenoid Biosynthesis: Ferraoxetane or Allyl Anion Mechanism for IspH Catalysis?
journal, May 2013
- Li, Jikun; Wang, Ke; Smirnova, Tatyana I.
- Angewandte Chemie International Edition, Vol. 52, Issue 25
X-ray structure of a novel matrix metalloproteinase inhibitor complexed to stromelysin
journal, May 2001
- Dunten, Pete; Kammlott, Ursula; Crowther, Robert
- Protein Science, Vol. 10, Issue 5
Probing the reaction mechanism of IspH protein by x-ray structure analysis
journal, December 2009
- Grawert, T.; Span, I.; Eisenreich, W.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 3
Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand Complexes
journal, October 2006
- Friesner, Richard A.; Murphy, Robert B.; Repasky, Matthew P.
- Journal of Medicinal Chemistry, Vol. 49, Issue 21
Crystal Structures of Mutant IspH Proteins Reveal a Rotation of the Substrate's Hydroxymethyl Group during Catalysis
journal, February 2012
- Span, Ingrid; Gräwert, Tobias; Bacher, Adelbert
- Journal of Molecular Biology, Vol. 416, Issue 1
Atomic-Resolution Structures of Discrete Stages on the Reaction Coordinate of the [Fe 4 S 4 ] Enzyme IspG (GcpE)
journal, June 2015
- Quitterer, Felix; Frank, Annika; Wang, Ke
- Journal of Molecular Biology, Vol. 427, Issue 12
Dynamics of the [4Fe-4S] Cluster in Pyrococcus furiosus D14C Ferredoxin via Nuclear Resonance Vibrational and Resonance Raman Spectroscopies, Force Field Simulations, and Density Functional Theory Calculations
journal, June 2011
- Mitra, Devrani; Pelmenschikov, Vladimir; Guo, Yisong
- Biochemistry, Vol. 50, Issue 23
Structure of ( E )-4-Hydroxy-3-methyl-but-2-enyl Diphosphate Reductase, the Terminal Enzyme of the Non-Mevalonate Pathway
journal, December 2008
- Rekittke, Ingo; Wiesner, Jochen; Röhrich, Rene
- Journal of the American Chemical Society, Vol. 130, Issue 51
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
journal, April 2010
- Baell, Jonathan B.; Holloway, Georgina A.
- Journal of Medicinal Chemistry, Vol. 53, Issue 7
Biosynthesis of Isoprene Units: Mössbauer Spectroscopy of Substrate and Inhibitor Binding to the [4Fe-4S] Cluster of the LytB/IspH Enzyme
journal, October 2011
- Ahrens-Botzong, Annegret; Janthawornpong, Karnjapan; Wolny, Juliusz A.
- Angewandte Chemie, Vol. 123, Issue 50
Synthesis of (−)-PNU-286607 by Asymmetric Cyclization of Alkylidene Barbiturates
journal, March 2009
- Ruble, J. Craig; Hurd, Alexander R.; Johnson, Timothy A.
- Journal of the American Chemical Society, Vol. 131, Issue 11
Monochromatization of synchrotron radiation for nuclear resonant scattering experiments
journal, January 2000
- Toellner, T. S.
- Hyperfine Interactions, Vol. 125, Issue 1/4, p. 3-28
Cysteine as a ligand platform in the biosynthesis of the FeFe hydrogenase H cluster
journal, August 2015
- Suess, Daniel L. M.; Bürstel, Ingmar; De La Paz, Liliana
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 37
The Stereochemical Course and Mechanism of the IspH Reaction
journal, March 2012
- Citron, Christian A.; Brock, Nelson L.; Rabe, Patrick
- Angewandte Chemie International Edition, Vol. 51, Issue 17
Structures of Fluoro, Amino, and Thiol Inhibitors Bound to the [Fe 4 S 4 ] Protein IspH
journal, January 2013
- Span, Ingrid; Wang, Ke; Wang, Weixue
- Angewandte Chemie International Edition, Vol. 52, Issue 7
Isoprenoidbiosynthese in pathogenen Bakterien: Nukleare inelastische Streuung ermöglicht Einblicke in den ungewöhnlichen [4Fe-4S]-Cluster vom E. - coli -Protein LytB/IspH
journal, June 2015
- Faus, Isabelle; Reinhard, Annegret; Rackwitz, Sergej
- Angewandte Chemie, Vol. 127, Issue 43
The 1.8-Å Crystal Structure of a Matrix Metalloproteinase 8-Barbiturate Inhibitor Complex Reveals a Previously Unobserved Mechanism for Collagenase Substrate Recognition
journal, January 2001
- Brandstetter, Hans; Grams, Frank; Glitz, Dagmar
- Journal of Biological Chemistry, Vol. 276, Issue 20
Nuclear resonance vibrational spectroscopy reveals the FeS cluster composition and active site vibrational properties of an O 2 -tolerant NAD + -reducing [NiFe] hydrogenase
journal, January 2015
- Lauterbach, Lars; Wang, Hongxin; Horch, Marius
- Chemical Science, Vol. 6, Issue 2
Cyanide Binding to the Novel 4Fe Ferredoxin from Pyrococcus furiosus: Investigation by EPR and ENDOR Spectroscopy
journal, May 1995
- Telser, Joshua; Smith, Eugene T.; Adams, Michael W. W.
- Journal of the American Chemical Society, Vol. 117, Issue 18
Phonon Density of States Measured by Inelastic Nuclear Resonant Scattering
journal, May 1995
- Sturhahn, W.; Toellner, T. S.; Alp, E. E.
- Physical Review Letters, Vol. 74, Issue 19
Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors
journal, June 2008
- Miller, A. A.; Bundy, G. L.; Mott, J. E.
- Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 8
Are Free Radicals Involved in IspH Catalysis? An EPR and Crystallographic Investigation
journal, June 2012
- Wang, Weixue; Wang, Ke; Span, Ingrid
- Journal of the American Chemical Society, Vol. 134, Issue 27
Bioorganometallic Chemistry with IspG and IspH: Structure, Function, and Inhibition of the [Fe 4 S 4 ] Proteins Involved in Isoprenoid Biosynthesis
journal, January 2014
- Wang, Weixue; Oldfield, Eric
- Angewandte Chemie International Edition, Vol. 53, Issue 17
Detektion von Fe-CN- und Fe-CO-Schwingungen im aktiven Zentrum der [NiFe]-Hydrogenase durch inelastische kernresonante Streuung
journal, November 2012
- Kamali, Saeed; Wang, Hongxin; Mitra, Devrani
- Angewandte Chemie, Vol. 125, Issue 2
Isoprenoid Biosynthesis: Ferraoxetane or Allyl Anion Mechanism for IspH Catalysis?
journal, May 2013
- Li, Jikun; Wang, Ke; Smirnova, Tatyana I.
- Angewandte Chemie, Vol. 125, Issue 25
Identification of Protein-Bound Dinitrosyl Iron Complexes by Nuclear Resonance Vibrational Spectroscopy
journal, May 2010
- Tonzetich, Zachary J.; Wang, Hongxin; Mitra, Devrani
- Journal of the American Chemical Society, Vol. 132, Issue 20
IspH-Protein von Escherichia coli - Struktur und Mechanismus
journal, July 2009
- Gräwert, Tobias; Rohdich, Felix; Span, Ingrid
- Angewandte Chemie, Vol. 121, Issue 31
Biosynthesis of Isoprene Units: Mössbauer Spectroscopy of Substrate and Inhibitor Binding to the [4Fe-4S] Cluster of the LytB/IspH Enzyme
journal, October 2011
- Ahrens-Botzong, Annegret; Janthawornpong, Karnjapan; Wolny, Juliusz A.
- Angewandte Chemie International Edition, Vol. 50, Issue 50
Comparative Isotropic Shifts, Redox Potentials, and Ligand Binding Propensities of [1:3] Site-Differentiated Cubane-Type [Fe 4 Q 4 ] 2+ Clusters (Q = S, Se)
journal, August 1997
- Zhou, Chaoyin; Holm, R. H.
- Inorganic Chemistry, Vol. 36, Issue 18
Structure of Active IspH Enzyme from Escherichia coli Provides Mechanistic Insights into Substrate Reduction
journal, July 2009
- Gräwert, Tobias; Rohdich, Felix; Span, Ingrid
- Angewandte Chemie International Edition, Vol. 48, Issue 31
EasySpin, a comprehensive software package for spectral simulation and analysis in EPR
journal, January 2006
- Stoll, Stefan; Schweiger, Arthur
- Journal of Magnetic Resonance, Vol. 178, Issue 1, p. 42-55
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1
journal, March 2001
- Lipinski, Christopher A.; Lombardo, Franco; Dominy, Beryl W.
- Advanced Drug Delivery Reviews, Vol. 46, Issue 1-3
Biologically related iron—sulfur clusters as reaction centers. Reduction of acetylene to ethylene in systems based on [Fe4S4(SR)4]3-
journal, January 1979
- McMillan, R. S.; Renaud, J.; Reynolds, John G.
- Journal of Inorganic Biochemistry, Vol. 11, Issue 3
Farnesyl Diphosphate Synthase Inhibitors from In Silico Screening
journal, May 2013
- Lindert, Steffen; Zhu, Wei; Liu, Yi-Liang
- Chemical Biology & Drug Design, Vol. 81, Issue 6
Biometallorganische Chemie mit IspG und IspH: Struktur, Funktion und Hemmung der an der Isoprenoid-Biosynthese beteiligten [Fe 4 S 4 ]-Proteine
journal, January 2014
- Wang, Weixue; Oldfield, Eric
- Angewandte Chemie, Vol. 126, Issue 17
Inhibition of IspH, a [4Fe–4S] 2+ Enzyme Involved in the Biosynthesis of Isoprenoids via the Methylerythritol Phosphate Pathway
journal, January 2013
- Janthawornpong, Karnjapan; Krasutsky, Sergiy; Chaignon, Philippe
- Journal of the American Chemical Society, Vol. 135, Issue 5
Fluor-, Amino- und Thiolinhibitoren im Komplex mit dem [Fe 4 S 4 ]-Protein IspH
journal, January 2013
- Span, Ingrid; Wang, Ke; Wang, Weixue
- Angewandte Chemie, Vol. 125, Issue 7
Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein
journal, June 2015
- Faus, Isabelle; Reinhard, Annegret; Rackwitz, Sergej
- Angewandte Chemie International Edition, Vol. 54, Issue 43
Raman Spectra of the Adducts of Reduced Species of [Fe 4 S 4 (SPh) 4 ] 2− and [Mo 2 Fe 6 S 8 (SPh) 9 ] 3− with Acetylene
journal, April 1987
- Tanaka, Koji; Nakamoto, Masami; Tsunomori, Michito
- Chemistry Letters, Vol. 16, Issue 4
Structure and Function of Four Classes of the 4Fe–4S Protein, IspH
journal, July 2016
- Rao, Guodong; Oldfield, Eric
- Biochemistry, Vol. 55, Issue 29
Der stereochemische Verlauf und Mechanismus der IspH-Reaktion
journal, March 2012
- Citron, Christian A.; Brock, Nelson L.; Rabe, Patrick
- Angewandte Chemie, Vol. 124, Issue 17
Discovery of acetylene hydratase activity of the iron–sulphur protein IspH
journal, January 2012
- Span, Ingrid; Wang, Ke; Wang, Weixue
- Nature Communications, Vol. 3, Issue 1