Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity

Kim, Youngchang; Makowska-Grzyska, Magdalena; Gorla, Suresh Kumar; Gollapalli, Deviprasad R.; Cuny, Gregory D.; Joachimiak, Andrzej; Hedstrom, Lizbeth

doi:10.1107/S2053230X15000187

Title: Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity

Abstract

Inosine 5´-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH (CpIMPDH) in complex with inosine 5´-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO₂ moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications.

Authors:

Kim, Youngchang ^[1]; Makowska-Grzyska, Magdalena ^[2]; Gorla, Suresh Kumar ^[3]; Gollapalli, Deviprasad R. ^[3]; Cuny, Gregory D. ^[4]; Joachimiak, Andrzej ^[1]; Hedstrom, Lizbeth ^[5]

Univ. of Chicago, Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases; Argonne National Laboratory, Argonne, IL (United States). Structural Biology Center.
Univ. of Chicago, Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases.
Brandeis Univ., Waltham, MA (United States). Dept. of Biology.
Univ. of Houston, Houston, TX (United States). Dept. of Pharmacological and Pharmaceutical Sciences.
Brandeis Univ., Waltham, MA (United States). Depts. of Biology and Chemistry.

Publication Date:: Tue Apr 21 00:00:00 EDT 2015

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID)

OSTI Identifier:: 1212708

Grant/Contract Number:: AC02-06CH11357

Resource Type:: Accepted Manuscript

Journal Name:: Acta Crystallographica. Section F, Structural Biology Communications

Additional Journal Information:: Journal Volume: 71; Journal Issue: 5; Journal ID: ISSN 2053-230X

Publisher:: International Union of Crystallography

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; Cryptosporidium; inosine 5′-monophosphate dehydrogenase; P131

Citation Formats


                    Kim, Youngchang, Makowska-Grzyska, Magdalena, Gorla, Suresh Kumar, Gollapalli, Deviprasad R., Cuny, Gregory D., Joachimiak, Andrzej, and Hedstrom, Lizbeth. Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.  United States: N. p., 2015. 
Web.  doi:10.1107/S2053230X15000187.

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                    Kim, Youngchang, Makowska-Grzyska, Magdalena, Gorla, Suresh Kumar, Gollapalli, Deviprasad R., Cuny, Gregory D., Joachimiak, Andrzej, & Hedstrom, Lizbeth. Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.  United States.  https://doi.org/10.1107/S2053230X15000187

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                    Kim, Youngchang, Makowska-Grzyska, Magdalena, Gorla, Suresh Kumar, Gollapalli, Deviprasad R., Cuny, Gregory D., Joachimiak, Andrzej, and Hedstrom, Lizbeth. Tue .  
"Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity".  United States.  https://doi.org/10.1107/S2053230X15000187.  https://www.osti.gov/servlets/purl/1212708.

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@article{osti_1212708,

  title        = {Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity},

  author       = {Kim, Youngchang and Makowska-Grzyska, Magdalena and Gorla, Suresh Kumar and Gollapalli, Deviprasad R. and Cuny, Gregory D. and Joachimiak, Andrzej and Hedstrom, Lizbeth},

  abstractNote = {Inosine 5´-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH (CpIMPDH) in complex with inosine 5´-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO2 moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications.},

  doi          = {10.1107/S2053230X15000187},

  journal      = {Acta Crystallographica. Section F, Structural Biology Communications},

  number       = 5,

  volume       = 71,

  place        = {United States},

  year         = {Tue Apr 21 00:00:00 EDT 2015},

  month        = {Tue Apr 21 00:00:00 EDT 2015}

}

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Works referencing / citing this record:

Inhibitors of inosine 5′-monophosphate dehydrogenase as emerging new generation antimicrobial agents
journal, January 2019

Juvale, Kapil; Shaik, Althaf; Kirubakaran, Sivapriya
MedChemComm, Vol. 10, Issue 8
DOI: 10.1039/c9md00179d

Cryptosporidium in humans and animals-a one health approach to prophylaxis
journal, September 2016

Ryan, U.; Zahedi, A.; Paparini, A.
Parasite Immunology, Vol. 38, Issue 9
DOI: 10.1111/pim.12350

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Title: Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity

Abstract

Citation Formats

Inhibitors of inosine 5′-monophosphate dehydrogenase as emerging new generation antimicrobial agents journal, January 2019

Cryptosporidium in humans and animals-a one health approach to prophylaxis journal, September 2016

Inhibitors of inosine 5′-monophosphate dehydrogenase as emerging new generation antimicrobial agents
journal, January 2019

Cryptosporidium in humans and animals-a one health approach to prophylaxis
journal, September 2016