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Unge, T
Alternative names
Publications (10 of 12) Show all publications
Kannan, K. K., Liljas, A., Liljas, L., Löfgren, S., Rossmann, M. G. & Unge, T. (2018). Bror Erik Strandberg (1930-2018) obituary. , 74
Open this publication in new window or tab >>Bror Erik Strandberg (1930-2018) obituary
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2018 (English)Other (Other (popular science, discussion, etc.))
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:uu:diva-366614 (URN)10.1107/S2059798318006708 (DOI)000437107900012 ()29968681 (PubMedID)
Note

Biographical item, in: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY

Volume: 74, Pages: 711-712, Part: 7

Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved
Nurbo, J., Ericsson, D. J., Rosenström, U., Muthas, D., Lindeberg, G., Unge, T. & Karlén, A. (2013). Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic – targeting Mycobacterium tuberculosis ribonucleotide reductase. Bioorganic & Medicinal Chemistry, 21(7), 1992-2000
Open this publication in new window or tab >>Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic – targeting Mycobacterium tuberculosis ribonucleotide reductase
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2013 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 21, no 7, p. 1992-2000Article in journal (Refereed) Published
Abstract [en]

Peptides mimicking the C-terminus of the small subunit (R2) of Mycobacterium tuberculosis ribonucleotide reductase (RNR) can compete for binding to the large subunit (R1) and thus inhibit RNR activity. Moreover, it has been suggested that the binding of the R2 C-terminus is very similar in M. tuberculosis and Salmonella typhimurium. Based on modeling studies of a crystal structure of the holocomplex of the S. typhimurium enzyme, a benzodiazepine-based turn mimetic was identified and a set of novel compounds incorporating the benzodiazepine scaffold was synthesized. The compounds were evaluated in a competitive fluorescence polarization assay and in an RNR activity assay. These studies revealed that the compounds incorporating the benzodiazepine scaffold have the ability to compete for the M. tuberculosis R2 binding site with low-micromolar affinity.

National Category
Biological Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-112341 (URN)10.1016/j.bmc.2013.01.020 (DOI)000316770300041 ()
Available from: 2010-01-26 Created: 2010-01-13 Last updated: 2017-12-12Bibliographically approved
Björkelid, C., Bergfors, T., Unge, T., Mowbray, S. L. & Jones, T. A. (2012). Structural studies on Mycobacterium tuberculosis DXR in complex with the antibiotic FR-900098. Acta Crystallographica Section D: Biological Crystallography, 68, 134-143
Open this publication in new window or tab >>Structural studies on Mycobacterium tuberculosis DXR in complex with the antibiotic FR-900098
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2012 (English)In: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 68, p. 134-143Article in journal (Refereed) Published
Abstract [en]

A number of pathogens, including the causative agents of tuberculosis and malaria, synthesize the essential isoprenoid precursor isopentenyl diphosphate via the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway rather than the classical mevalonate pathway that is found in humans. As part of a structure-based drug-discovery program against tuberculosis, DXR, the enzyme that carries out the second step in the MEP pathway, has been investigated. This enzyme is the target for the antibiotic fosmidomycin and its active acetyl derivative FR-900098. The structure of DXR from Mycobacterium tuberculosis in complex with FR-900098, manganese and the NADPH cofactor has been solved and refined. This is a new crystal form that diffracts to a higher resolution than any other DXR complex reported to date. Comparisons with other ternary complexes show that the conformation is that of the enzyme in an active state: the active-site flap is well defined and the cofactor-binding domain has a conformation that brings the NADPH into the active site in a manner suitable for catalysis. The substrate-binding site is highly conserved in a number of pathogens that use this pathway, so any new inhibitor that is designed for the M. tuberculosis enzyme is likely to exhibit broad-spectrum activity.

Keywords
tuberculosis, DXR, IspC, MEP pathway
National Category
Medical and Health Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-169337 (URN)10.1107/S0907444911052231 (DOI)000299469100006 ()
Available from: 2012-03-05 Created: 2012-02-28 Last updated: 2017-12-07Bibliographically approved
Mahalingam, A. K., Axelsson, L., Ekegren, J. K., Wannberg, J., Kihlström, J., Unge, T., . . . Hallberg, A. (2010). HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells. Journal of Medicinal Chemistry, 53(2), 607-615
Open this publication in new window or tab >>HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 2, p. 607-615Article in journal (Refereed) Published
Abstract [en]

By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-137907 (URN)10.1021/jm901165g (DOI)000273672100007 ()
Available from: 2010-12-17 Created: 2010-12-16 Last updated: 2018-01-12Bibliographically approved
Nurbo, J., Roos, A. K., Muthas, D., Wahlström, E., Ericsson, D. J., Lundstedt, T., . . . Karlén, A. (2007). Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase. Journal of Peptide Science, 13(12), 822-832
Open this publication in new window or tab >>Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
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2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 12, p. 822-832Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that TrP5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain., as compared to Trp5.

Keywords
mycobacterium tuberculosis, ribonucleotide reductase, peptide inhibitors, alanine scan, statistical molecular design, structure activity relationships, FHDoE
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-14261 (URN)10.1002/psc.906 (DOI)000252000600007 ()17918768 (PubMedID)
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
Henriksson, L. M., Unge, T., Carlsson, J., Åqvist, J., Mowbray, S. L. & Jones, T. A. (2007). Structures of Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase provide new insights into catalysis. Journal of Biological Chemistry, 282(27), 19905-19916
Open this publication in new window or tab >>Structures of Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase provide new insights into catalysis
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2007 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 27, p. 19905-19916Article in journal (Refereed) Published
Abstract [en]

Isopentenyl diphosphate is the precursor of various isoprenoids that are essential to all living organisms. It is produced by the mevalonate pathway in humans but by an alternate route in plants, protozoa, and many bacteria. 1-Deoxy-D-xylulose-5-phosphate reductoisomerase catalyzes the second step of this non-mevalonate pathway, which involves an NADPH-dependent rearrangement and reduction of 1-deoxy-D-xylulose 5-phosphate to form 2-C-methyl-D-erythritol 4-phosphate. The use of different pathways, combined with the reported essentiality of the enzyme makes the reductoisomerase a highly promising target for drug design. Here we present several high resolution structures of the Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase, representing both wild type and mutant enzyme in various complexes with Mn2+, NADPH, and the known inhibitor fosmidomycin. The asymmetric unit corresponds to the biological homodimer. Although crystal contacts stabilize an open active site in the B molecule, the A molecule displays a closed conformation, with some differences depending on the ligands bound. An inhibition study with fosmidomycin resulted in an estimated IC50 value of 80 nM. The double mutant enzyme (D151N/E222Q) has lost its ability to bind the metal and, thereby, also its activity. Our structural information complemented with molecular dynamics simulations and free energy calculations provides the framework for the design of new inhibitors and gives new insights into the reaction mechanism. The conformation of fosmidomycin bound to the metal ion is different from that reported in a previously published structure and indicates that a rearrangement of the intermediate is not required during catalysis.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-96293 (URN)10.1074/jbc.M701935200 (DOI)000247650600065 ()17491006 (PubMedID)
Available from: 2007-10-19 Created: 2007-10-19 Last updated: 2017-12-14Bibliographically approved
Ekegren, J. K., Ginman, N., Johansson, Å., Wallberg, H., Larhed, M., Samuelsson, B., . . . Hallberg, A. (2006). Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold. Journal of Medicinal Chemistry, 49(5), 1828-1832
Open this publication in new window or tab >>Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold
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2006 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 49, no 5, p. 1828-1832Article in journal (Refereed) Published
Abstract [en]

Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-24527 (URN)10.1021/jm051239z (DOI)000236005400033 ()16509598 (PubMedID)
Available from: 2008-01-29 Created: 2008-01-29 Last updated: 2018-01-12Bibliographically approved
Roos, A. K., Andersson, C. E., Bergfors, T., Jacobsson, M., Karlén, A., Unge, T., . . . Mowbray, S. L. (2004). Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site.. J Mol Biol, 335(3), 799-809
Open this publication in new window or tab >>Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site.
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2004 (English)In: J Mol Biol, ISSN 0022-2836, Vol. 335, no 3, p. 799-809Article in journal (Refereed) Published
Keywords
Aldose-Ketose Isomerases/*chemistry, Amino Acid Sequence, Binding Sites, Crystallography; X-Ray, Models; Molecular, Molecular Structure, Mycobacterium tuberculosis/*enzymology, Protein Structure; Tertiary, Research Support; Non-U.S. Gov't, Sequence Alignment
Identifiers
urn:nbn:se:uu:diva-71658 (URN)14687575 (PubMedID)
Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2016-05-09
Henriksson, L. M., Johansson, P., Unge, T. & Mowbray, S. L. (2004). X-ray structure of peptidyl-prolyl cis-trans isomerase A from Mycobacterium tuberculosis.. Eur J Biochem, 271(20), 4107-13
Open this publication in new window or tab >>X-ray structure of peptidyl-prolyl cis-trans isomerase A from Mycobacterium tuberculosis.
2004 (English)In: Eur J Biochem, ISSN 0014-2956, Vol. 271, no 20, p. 4107-13Article in journal (Refereed) Published
Keywords
Amino Acid Sequence, Bacterial Proteins/chemistry/genetics/metabolism, Comparative Study, Crystallography; X-Ray, Cyclophilin A/*chemistry/genetics/metabolism, Humans, Isomerism, Kinetics, Models; Molecular, Molecular Sequence Data, Mycobacterium tuberculosis/*enzymology, Oligopeptides/chemistry/metabolism, Protein Conformation, Recombinant Proteins/chemistry/genetics/metabolism, Research Support; Non-U.S. Gov't, Sequence Alignment, Spectrophotometry/methods
Identifiers
urn:nbn:se:uu:diva-71664 (URN)15479239 (PubMedID)
Available from: 2005-05-11 Created: 2005-05-11 Last updated: 2016-05-09
Alterman, M., Andersson, H. O., Garg, N., Ahlsén, G., Lövgren, S., Classon, B., . . . Hallberg, A. (1999). Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1'-modified HIV-1 protease inhibitors. Journal of Medicinal Chemistry, 42(19), 3835-3844
Open this publication in new window or tab >>Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1'-modified HIV-1 protease inhibitors
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1999 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 42, no 19, p. 3835-3844Article in journal (Refereed) Published
Keywords
DEFICIENCY SYNDROME AIDS; ANTIVIRAL ACTIVITY; DRUG-DESIGN; DIFLUOROSTATONE TYPE; SIDE-CHAIN; VIRUS; PROTEINASE; RESISTANCE; WATER; INFECTION
National Category
Pharmaceutical Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-51139 (URN)10.1021/jm9910371 (DOI)
Available from: 2007-02-07 Created: 2007-02-07 Last updated: 2018-01-11Bibliographically approved
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