Identification of a Unique Inhibitor-Binding Site on Choline Kinase α

Kall, Stefanie L.; Delikatny, Edward J.; Lavie, Arnon

doi:10.1021/acs.biochem.7b01257

Title: Identification of a Unique Inhibitor-Binding Site on Choline Kinase α

Journal Article · Thu Feb 01 00:00:00 EST 2018 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.7b01257· OSTI ID:1432889

Kall, Stefanie L. ^[1]; Delikatny, Edward J. ^[2];

^[3]

Univ. of Illinois at Chicago, IL (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States)
Univ. of Illinois at Chicago, IL (United States); The Jesse Brown VA Medical Center, Chicago, IL (United States)

Choline kinase α (ChoKα) is an enzyme that is upregulated in many types of cancer and has been shown to be tumorigenic. As such, it makes a promising target for inhibiting tumor growth. Though there have been several inhibitors synthesized for ChoKα, not all of them demonstrate the same efficacy in vivo, though the reasons behind this difference in potency are not clear. One particular inhibitor, designated TCD-717, has recently completed phase I clinical trials. Cell culture and in vitro studies support the powerful inhibitory effect TCD-717 has on ChoKα, but an examination of the inhibitor’s interaction with the ChoKα enzyme has been missing prior to this work. Here we detail the 2.35 Å structure of ChoKα in complex with TCD-717. Examination of this structure in conjunction with kinetic assays reveals that TCD-717 does not bind directly in the choline pocket as do previously characterized ChoKα inhibitors, but rather in a proximal but novel location near the surface of the enzyme. Here, the unique binding site identified for TCD-717 lends insight for the future design of more potent in vivo inhibitors for ChoKα.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); Michigan Economic Development Corp.; Michigan Technology Tri-Corridor; National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; 085P1000817; RO1 EB013685; R01 EB018645

OSTI ID:: 1432889

Journal Information:: Biochemistry, Vol. 57, Issue 8; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 18 works

Citation information provided by
Web of Science

References (28)

Structure and function of choline kinase isoforms in mammalian cells Aoyama, C. Progress in Lipid Research, Vol. 43, Issue 3 https://doi.org/10.1016/j.plipres.2003.12.001	journal	May 2004
Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1 Serrán-Aguilera, Lucía; Nuti, Roberto; López-Cara, Luisa C. Molecular Informatics, Vol. 34, Issue 6-7 https://doi.org/10.1002/minf.201400140	journal	June 2015
Choline kinase alpha—Putting the ChoK-hold on tumor metabolism Arlauckas, Sean P.; Popov, Anatoliy V.; Delikatny, E. James Progress in Lipid Research, Vol. 63 https://doi.org/10.1016/j.plipres.2016.03.005	journal	July 2016
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Choline Kinase Is a Novel Oncogene that Potentiates RhoA-Induced Carcinogenesis Ramírez de Molina, Ana; Gallego-Ortega, David; Sarmentero, Jacinto Cancer Research, Vol. 65, Issue 13 https://doi.org/10.1158/0008-5472.CAN-04-4416	journal	July 2005
Discovery of a New Binding Site on Human Choline Kinase α1: Design, Synthesis, Crystallographic Studies, and Biological Evaluation of Asymmetrical Bispyridinium Derivatives Rubio-Ruiz, Belén; Figuerola-Conchas, Ainoa; Ramos-Torrecillas, Javier Journal of Medicinal Chemistry, Vol. 57, Issue 2 https://doi.org/10.1021/jm401665x	journal	September 2013
Choline kinase inhibitors as a novel approach for antiproliferative drug design Hernández-Alcoceba, Rubén; Saniger, Luisa; Campos, Joaquín Oncogene, Vol. 15, Issue 19 https://doi.org/10.1038/sj.onc.1201414	journal	November 1997
Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery Zech, Stephan G.; Kohlmann, Anna; Zhou, Tianjun Journal of Medicinal Chemistry, Vol. 59, Issue 2 https://doi.org/10.1021/acs.jmedchem.5b01552	journal	January 2016
Determination of Potential Scaffolds for Human Choline Kinase α1 by Chemical Deconvolution Studies Sahún-Roncero, María; Rubio-Ruíz, Belén; Conejo-García, Ana ChemBioChem, Vol. 14, Issue 11 https://doi.org/10.1002/cbic.201300195	journal	June 2013
Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers Ramı́rez de Molina, Ana; Rodrı́guez-González, Agustı́n; Gutiérrez, Ruth Biochemical and Biophysical Research Communications, Vol. 296, Issue 3 https://doi.org/10.1016/S0006-291X(02)00920-8	journal	August 2002
Functional interactions between Choline kinase α, epidermal growth factor receptor and c-Src in breast cancer cell proliferation Miyake, T.; Parsons, S. J. Oncogene, Vol. 31, Issue 11 https://doi.org/10.1038/onc.2011.332	journal	August 2011
Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors Kumar, Manoj; Arlauckas, Sean P.; Saksena, Sona Molecular Cancer Therapeutics, Vol. 14, Issue 4 https://doi.org/10.1158/1535-7163.MCT-14-0775	journal	February 2015
Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma Hu, Liang; Wang, Ruo-Yu; Cai, Jian Oncotarget, Vol. 7, Issue 41 https://doi.org/10.18632/oncotarget.11433	journal	August 2016
Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells Lacal, J. C.; Campos, J. M. Molecular Cancer Therapeutics, Vol. 14, Issue 1 https://doi.org/10.1158/1535-7163.MCT-14-0531	journal	December 2014
Choline kinase-α protein and phosphatidylcholine but not phosphocholine are required for breast cancer cell survival: Role of choline kinase-alpha in breast cancer Mori, Noriko; Wildes, Flonné; Kakkad, Samata NMR in Biomedicine, Vol. 28, Issue 12 https://doi.org/10.1002/nbm.3429	journal	October 2015
Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3: SINGLE AMINO ACID NEAR THE ACTIVE SITE INFLUENCES INHIBITOR SENSITIVITY Hong, Bum Soo; Allali-Hassani, Abdellah; Tempel, Wolfram Journal of Biological Chemistry, Vol. 285, Issue 21 https://doi.org/10.1074/jbc.M109.039024	journal	March 2010
Elucidation of Human Choline Kinase Crystal Structures in Complex with the Products ADP or Phosphocholine Malito, Enrico; Sekulic, Nikolina; Too, Wei Cun See Journal of Molecular Biology, Vol. 364, Issue 2 https://doi.org/10.1016/j.jmb.2006.08.084	journal	November 2006
Noninvasive Magnetic Resonance Spectroscopic Pharmacodynamic Markers of the Choline Kinase Inhibitor MN58b in Human Carcinoma Models Al-Saffar, Nada M. S.; Troy, Helen; de Molina, Ana Ramírez Cancer Research, Vol. 66, Issue 1 https://doi.org/10.1158/0008-5472.CAN-05-1338	journal	January 2006
Choline metabolism in malignant transformation Glunde, Kristine; Bhujwalla, Zaver M.; Ronen, Sabrina M. Nature Reviews Cancer, Vol. 11, Issue 12 https://doi.org/10.1038/nrc3162	journal	November 2011
Structure-activity aspects of hemicholinium-3 (HC-3) and its analogs and congeners Cannon, Joseph G. Medicinal Research Reviews, Vol. 14, Issue 5 https://doi.org/10.1002/med.2610140503	journal	September 1994
A non-catalytic role of choline kinase alpha is important in promoting cancer cell survival Falcon, S. C.; Hudson, C. S.; Huang, Y. Oncogenesis, Vol. 2, Issue 3 https://doi.org/10.1038/oncsis.2013.2	journal	March 2013
Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy Ramírez de Molina, Ana; Gutiérrez, Ruth; Ramos, Maria Angeles Oncogene, Vol. 21, Issue 27 https://doi.org/10.1038/sj.onc.1205556	journal	June 2002
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1) Schiaffino-Ortega, Santiago; Baglioni, Eleonora; Mariotto, Elena Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep23793	journal	March 2016
Antiplasmodial Activity and Mechanism of Action of RSM-932A, a Promising Synergistic Inhibitor of Plasmodium falciparum Choline Kinase Zimmerman, Tahl; Moneriz, Carlos; Diez, Amalia Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 12 https://doi.org/10.1128/AAC.00920-13	journal	September 2013
The Mechanism of Allosteric Coupling in Choline Kinase α1 Revealed by the Action of a Rationally Designed Inhibitor Sahún-Roncero, María; Rubio-Ruiz, Belén; Saladino, Giorgio Angewandte Chemie International Edition, Vol. 52, Issue 17 https://doi.org/10.1002/anie.201209660	journal	February 2013
Kinetic and mechanistic characterisation of Choline Kinase-α Hudson, Catherine S.; Knegtel, Ronald M.; Brown, Kieron Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834, Issue 6 https://doi.org/10.1016/j.bbapap.2013.02.008	journal	June 2013
Choline Phosphokinase Wittenberg, Jonathan; Kornberg, Arthur Journal of Biological Chemistry, Vol. 202, Issue 1 https://doi.org/10.1016/S0021-9258(19)57144-7	journal	May 1953

Cited By (3)

Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase Kall, Stefanie L.; Whitlatch, Kindra; Smithgall, Thomas E. Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-53447-0	journal	November 2019
Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer Sonkar, Kanchan; Ayyappan, Vinay; Tressler, Caitlin M. NMR in Biomedicine, Vol. 32, Issue 10 https://doi.org/10.1002/nbm.4112	journal	August 2018
Causes, consequences, and therapy of tumors acidosis Pillai, Smitha R.; Damaghi, Mehdi; Marunaka, Yoshinori Cancer and Metastasis Reviews, Vol. 38, Issue 1-2 https://doi.org/10.1007/s10555-019-09792-7	journal	March 2019

Similar Records

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3 Single Amino Acid near the Active Site Influences Inhibitor Sensitivity

Journal Article · Tue Jul 06 00:00:00 EDT 2010 · J. Biol. Chem. · OSTI ID:1432889

Hong, Bum Soo; Allali-Hassani, Abdellah; Tempel, Wolfram; +4 more

Studies on (/sup 3/H) hemicholinium-3 ((/sup 3/H)HC-3), (/sup 3/H) pirenzepine ((/sup 3/H)PZ) and (/sup 3/H)(-)quinuclidinyl benzilate ((/sup 3/H)(-)QNB) binding with choline and acetylcholine analogues (AF30, AF64, AF64A)

Conference · Wed Mar 05 00:00:00 EST 1986 · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) · OSTI ID:1432889

Gulva, K; Fisher, A; Hanin, I; +1 more

Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase

Journal Article · Tue Nov 19 00:00:00 EST 2019 · Scientific Reports · OSTI ID:1432889

Kall, Stefanie L.; Whitlatch, Kindra; Smithgall, Thomas E.; +1 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
chemical structure
nutrition
inhibitors
organic compounds
peptides and proteins
human choline kinase
TCD-717
crystal structure
binding site
cancer drug

Title: Identification of a Unique Inhibitor-Binding Site on Choline Kinase α

Citation Formats

References (28)

Cited By (3)

Similar Records

Related Subjects