Dmitry M. Korzhnev, PhDAssociate Professor, Department of Molecular Biology and Biophysics
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Degree | Institution | Major |
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MS | Moscow Institute of Physics and Technology | Applied Physics and Mathematics |
PhD | Moscow Institute of Physics and Technology | Biophysics |
Post-Graduate Training
Training | Institution | Specialty |
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Postdoctoral | Swedish NMR Centre at Göteborg University | Post-Doctoral Fellow in Structural Biology in Swedish NMR Centre at Göteborg University under supervision of Prof. M. Billeter |
Postdoctoral | Shemyakin-Ovchinnikov Inst. Bioorganic Chemistry | Research training in Structural Biology under supervision of Prof. A.S. Arseniev |
Postdoctoral | University of Toronto | Post-Doctoral Fellow in Structural Biology (NMR) under supervision of Prof. L.E. Kay |
The primary focus of my laboratory is studies of protein structure, dynamics and interactions using structural biology methods, including nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography. We make use of cutting-edge TROSY-NMR techniques that allow to access structural dynamics and interactions of protein assemblies with molecular weights of up to 1 MDa, opening an avenue for deciphering molecular mechanisms of their action.
The underlying cause of cancer is spontaneous mutations introduced to genomic DNA. Reactive products of cellular metabolism and external genotoxic agents cause persistent DNA damage, which is constantly removed through various DNA repair mechanisms. It is unavoidable, however, that some DNA modifications (lesions) persist into S-phase, creating blocks for progression of the DNA replication machinery. To circumvent this problem organisms in all kingdoms of life have evolved DNA damage tolerance pathways, employing specialized enzymes that bypass DNA lesions while temporarily leaving DNA damage unrepaired. The vast majority of mutations are introduced in the genome by enzymes of error-prone branch of DNA damage tolerance - translesion DNA synthesis (TLS). Genetic changes that ensue as a result of TLS are at the root of the onset of cancer and the development of various resistance mechanisms displayed by relapsed tumors, which represents a major problem for treatment of some types of cancer, including ovarian and lung. Our research is aimed at obtaining a detailed atomic-resolution picture of structure, dynamics and interactions of proteins and protein assemblies involved in DNA damage tolerance pathways that will aid the development of new strategies for cancer therapy.
Intermediate and transition states of biomolecular processes represent a paradigm of functionally important structure in biology. For example, protein self-assembly involves the formation of partially folded and misfolded protein states prone to aggregation implicated in a number of human disorders, including type-II diabetes, Alzheimer's and Parkinson's diseases. Although the characterization of such species can provide vital clues about the mechanisms of the underlying processes, it is extremely challenging to examine such states because they are populated at low levels and are not readily isolated. One of the research directions in my laboratory is studies of intermediate and transition states of protein folding and binding using novel NMR relaxation dispersion methodology.
Accepting Lab Rotation Students: Fall Block 2024, Spring 1 and 2 Block 2025
Lab Rotation Projects
- Structure, dynamics and interactions of proteins involved in DNA damage tolerance pathways
- Studying folding mechanisms of single-domain proteins. Structure determination of folding intermediates
Journal Articles
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Lead compound profiling for small molecule inhibitors of the REV1-CT/RIR Translesion synthesis Protein-Protein interaction.
Bioorganic & medicinal chemistry 2024 May;106117755
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Effects of Xylanase A double mutation on substrate specificity and structural dynamics.
Journal of structural biology 2024 Mar;216(2):108082
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Conformational exchange at a C2H2 zinc-binding site facilitates redox sensing by the PML protein.
Structure (London, England : 1993) 2023 Jul;
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Backbone and ILV side-chain methyl NMR resonance assignments of human Rev7/Rev3-RBM1 and Rev7/Rev3-RBM2 complexes.
Biomolecular NMR assignments 2023 Jun;17(1):107-114
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Evolution of Rev7 interactions in eukaryotic TLS DNA polymerase Polζ.
The Journal of biological chemistry 2022 Dec;299(2):102859
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ILV methyl NMR resonance assignments of the 81 kDa E. coli β-clamp.
Biomolecular NMR assignments 2022 Jun;
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DNA Sequence Specificity Reveals a Role of the HLTF HIRAN Domain in the Recognition of Trinucleotide Repeats.
Biochemistry 2022 May;
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Backbone and ILV side-chain NMR resonance assignments of the catalytic domain of human deubiquitinating enzyme USP7.
Biomolecular NMR assignments 2022 May;
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Architecture of the two metal-binding sites in prolactin.
Biophysical journal 2022 Feb;
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NMR resonance assignments for the nucleotide binding domains of the E. coli clamp loader complex γ subunit.
Biomolecular NMR assignments 2021 Mar;
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Structure-based drug design of phenazopyridine derivatives as inhibitors of Rev1 interactions in translesion synthesis.
ChemMedChem 2020 Dec;
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Virtual Pharmacophore Screening Identifies Small-Molecule Inhibitors of the Rev1-CT/RIR Protein-Protein Interaction.
ChemMedChem 2019 Sep;14(17):1610-1617
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Dynamics of the E. coli β-Clamp Dimer Interface and Its Influence on DNA Loading.
Biophysical journal 2019 Jul;
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Structural Approach To Identify a Lead Scaffold That Targets the Translesion Synthesis Polymerase Rev1.
Journal of chemical information and modeling 2018 Oct;582266-2277
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Conformational Dynamics of a Cysteine-Stabilized Plant Defensin Reveals an Evolutionary Mechanism to Expose Hydrophobic Residues.
Biochemistry 2018 Sep;575797-5806
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Rev7 dimerization is important for assembly and function of the Rev1/Polζ translesion synthesis complex.
Proceedings of the National Academy of Sciences of the United States of America 2018 Aug;115(35):E8191-E8200
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Small molecule scaffolds that disrupt the Rev1-CT/RIR protein-protein interaction.
Bioorganic & medicinal chemistry 2018 Aug;26(14):4301-4309
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Identification of Small Molecule Translesion Synthesis Inhibitors That Target the Rev1-CT/RIR Protein-Protein Interaction.
ACS Chemical Biology 2017 Jun;12(7):1903-1912
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Structural Characterization of the Early Events in the Nucleation-Condensation Mechanism in a Protein Folding Process.
Journal of the American Chemical Society 2017 May;139(20):6899-6910
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NMR resonance assignments for the N-terminal domain of the δ subunit of the E. coli γ clamp loader complex.
Biomolecular NMR Assignments 2017 Mar;11(2):169-173
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Solution NMR structure of the HLTF HIRAN domain: a conserved module in SWI2/SNF2 DNA damage tolerance proteins.
Journal of Biomolecular NMR 2016 Oct;66(3):209-219
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Targeting the Translesion Synthesis Pathway for the Development of Anti-Cancer Chemotherapeutics.
Journal of Medicinal Chemistry 2016 Jul;59(20):9321-9336
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Interaction between the Rev1 C-Terminal Domain and the PolD3 Subunit of Polζ Suggests a Mechanism of Polymerase Exchange upon Rev1/Polζ-Dependent Translesion Synthesis.
Biochemistry 2016 Apr;55(13):2043-53
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Probing the Residual Structure of the Low Populated Denatured State of ADA2h under Folding Conditions by Relaxation Dispersion Nuclear Magnetic Resonance Spectroscopy.
Biochemistry 2015 Aug;54(30):4611-22
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Structural Characterization of Interaction between Human Ubiquitin-specific Protease 7 and Immediate-Early Protein ICP0 of Herpes Simplex Virus-1.
Journal of Biological Chemistry 2015 Jul;290(38):22907-22918
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HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal.
Molecular Cell 2015 Jun;58(6):1090-1100
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NMR structure of the human Rad18 zinc finger in complex with ubiquitin defines a class of UBZ domains in proteins linked to the DNA damage response.
Biochemistry 2014 Sep;53(37):5895-906
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NMR mapping of PCNA interaction with translesion synthesis DNA polymerase Rev1 mediated by Rev1-BRCT domain.
Journal of molecular biology 2013 Sep;425(17):3091-105
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PHD domain from human SHPRH.
Journal of biomolecular NMR 2013 Aug;56(4):393-9
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Loss of structure-gain of function.
Journal of molecular biology 2013 Jan;425(1):17-8
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Transiently populated intermediate functions as a branching point of the FF domain folding pathway.
Proceedings of the National Academy of Sciences of the United States of America 2012 Oct;109(44):17777-82
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The C-terminal domain of human Rev1 contains independent binding sites for DNA polymerase η and Rev7 subunit of polymerase ζ.
FEBS letters 2012 Sep;586(19):3051-6
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NMR structure and dynamics of the C-terminal domain from human Rev1 and its complex with Rev1 interacting region of DNA polymerase η.
Biochemistry 2012 Jul;51(27):5506-20
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Cross-validation of the structure of a transiently formed and low populated FF domain folding intermediate determined by relaxation dispersion NMR and CS-Rosetta.
The journal of physical chemistry. B 2012 Jun;116(23):6637-44
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Nonnative interactions in the FF domain folding pathway from an atomic resolution structure of a sparsely populated intermediate: an NMR relaxation dispersion study.
Journal of the American Chemical Society 2011 Jan;133(28):10974-82
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NMR characterization of copper-binding domains 4-6 of ATP7B .
Biochemistry 2010 Oct;49(39):8468-77
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A transient and low-populated protein-folding intermediate at atomic resolution.
Science (New York, N.Y.) 2010 Sep;329(5997):1312-6
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A simple method for measuring signs of 1HN chemical shift differences between ground and excited protein states
Journal of Biomolecular NMR 2010 Jan;47135-141
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Measurement of signs of chemical shift differences between ground and excited protein states: a comparison between H(S/M)QC and R1-rho methods
Journal of Biomolecular NMR 2010 Jan;46205-216
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Alternate binding modes for a ubiquitin-SH3 domain interaction studied by NMR spectroscopy.
Journal of molecular biology 2009 Feb;386(2):391-405
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An analysis of the effects of 1HN-1HN dipolar couplings on the measurement of amide bond vector orientations in invisible protein states by relaxation dispersion NMR
Journal of Physical Chemistry B 2009 Jan;113(29):9968-9977
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Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain.
Proceedings of the National Academy of Sciences of the United States of America 2007 Sep;104(36):14336-41
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Propagation of dynamic changes in barnase upon binding of barstar: an NMR and computational study.
Journal of molecular biology 2007 Apr;367(4):1079-92
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The folding pathway of an FF domain: Characterization of an on-pathway intermediate state under folding conditions by 15N, 13Ca and 13C-methyl relaxation dispersion and 1H/2H-exchange NMR spectroscopy
Journal of Molecular Biology 2007 Jan;372(2):497-512
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Abp1p and Fyn SH3 domains fold through similar low-populated intermediate states.
Biochemistry 2006 Aug;45(34):10175-83
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Assessment of the effects of increased relaxation dispersion data on the extraction of 3-site exchange parameters characterizing the unfolding of an SH3 domain.
Journal of biomolecular NMR 2006 Mar;34(3):129-35
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Hydration and packing along the folding pathway of SH3 domains by pressure-dependent NMR.
Biochemistry 2006 Jan;45(15):4711-9
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Probing the transition state ensemble of a protein folding reaction by pressure-dependent NMR relaxation dispersion.
Journal of the American Chemical Society 2006 Jan;128(15):5262-9
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Side-chain interactions in the folding pathway of a Fyn SH3 domain mutant studied by relaxation dispersion NMR spectroscopy.
Biochemistry 2005 Nov;44(47):15430-6
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Intrinsic dynamics of an enzyme underlies catalysis.
Nature 2005 Nov;438(7064):117-21
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Cross-correlated spin relaxation effects in methyl 1H CPMG-based relaxation dispersion experiments: complications and a simple solution.
Journal of biomolecular NMR 2005 Apr;31(4):337-42
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Multiple-site exchange in proteins studied with a suite of six NMR relaxation dispersion experiments: an application to the folding of a Fyn SH3 domain mutant.
Journal of the American Chemical Society 2005 Jan;127(44):15602-11
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Off-resonance R1-rho NMR studies of exchange dynamics in proteins with low spin-lock fields: An application to a Fyn SH3 domain
Journal of the American Chemical Society 2005 Jan;127713-721
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Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR.
Nature 2004 Jul;430(6999):586-90
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Multiple-quantum relaxation dispersion NMR spectroscopy probing millisecond time-scale dynamics in proteins: theory and application.
Journal of the American Chemical Society 2004 Jun;126(23):7320-9
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From structure and dynamics of protein L7/L12 to molecular switching in ribosome.
The Journal of biological chemistry 2004 Apr;279(17):17697-706
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Double- and zero-quantum NMR relaxation dispersion experiments sampling millisecond time scale dynamics in proteins.
Journal of the American Chemical Society 2004 Feb;126(6):1886-91
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Dramatic acceleration of protein folding by stabilization of a nonnative backbone conformation.
Proceedings of the National Academy of Sciences of the United States of America 2004 Jan;101(21):7954-9
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Gated electron transfers and electron pathways in azurin: A NMR dynamic study at multiple fields and temperatures
Journal of Molecular Biology 2004 Jan;3421599-1611
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NMR detection of multiple transitions to low-populated states in azurin.
Protein science : a publication of the Protein Society 2003 Jan;12(1):56-65
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Off-resonance R1-rho relaxation outside of the fast exchange limit: An experimental study of a cavity mutant of T4 lysozyme
Journal of Biomolecular NMR 2003 Jan;2639-48
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An NMR experiment for the accurate measurement of heteronuclear spin-lock relaxation rates.
Journal of the American Chemical Society 2002 Sep;124(36):10743-53
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Dynamics-modulated biological activity of transforming growth factor b3
Journal of Biological Chemistry 2002 Jan;27746273-46279
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Backbone dynamics of the channel-forming antibiotic zervamicin IIB studied by 15N NMR relaxation.
FEBS letters 2001 Apr;495(1-2):52-5
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MUNIN: Application of three-way decomposition to the analysis of heteronuclear NMR relaxation data
Journal of Biomolecular NMR 2001 Jan;21263-268
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Off-resonance effects in 15N T2 CPMG measurements
Journal of Biomolecular NMR 2000 Jan;17231-237
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Sampling of protein dynamics in nanosecond time scale by 15N NMR relaxation and self-diffusion measurements.
Journal of biomolecular structure & dynamics 1999 Aug;17(1):157-74
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1H-15N NMR dynamic study of an isolated a-helical peptide (1-36)-bacteriorhodopsin reveals the equilibrium helix-coil transitions.
Journal of Biomolecular NMR 1999 Jan;14345-356
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Mechanism of the unfolding of transmembrane ?-helical segment (1-36)-bacteriorhodopsin studied by molecular dynamics simulations
Journal of Physical Chemistry B 1999 Jan;1037036-7043
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The effect of helix-coil transition on backbone 15N NMR relaxation of isolated transmembrane segment (1-36)-bacteriorhodopsin
Journal of Biomolecular NMR 1999 Jan;14357-368
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Model-free approach beyond the borders of its applicability.
Journal of magnetic resonance (San Diego, Calif. : 1997) 1997 Aug;127(2):184-91
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Backbone dynamics of (1-71)- and (1-36) bacterioopsin studied by two-dimensional 1H-15N NMR spectroscopy.
Journal of Biomolecular NMR 1995 Jan;6113 -122
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Manifestation of intramolecular motions on pico- and nanosecond time scales in 1H-15N NMR relaxation: Analysis of dynamics model of one- and two- helical subunits of bacterioopsin
Journal of Biomolecular NMR 1995 Jan;5383-396
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Processing of heteronuclear NMR relaxation data with the new software DASHA
Applied Magnetic Resonance 1995 Jan;9 581-588
Book Chapters
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NMR study of bacteriorhodopsin structure and dynamics
Protein Structures: Kaleidoscope of Structural Properties and Functions 2003 Jan;273-297
Reviews
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Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.
RSC chemical biology 2021 Aug;2(4):1167-1195
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Protein folding by NMR.
Progress in Nuclear Magnetic Resonance Spectroscopy 2017 May;10052-77
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Probing invisible, low-populated States of protein molecules by relaxation dispersion NMR spectroscopy: an application to protein folding.
Accounts of chemical research 2008 Mar;41(3):442-51
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NMR studies of Brownian tumbling and internal motions in proteins
Progress in Nuclear Magnetic Resonance Spectroscopy 2001 Jan;38197-266