Ivaylo Ivanov

Ivaylo Ivanov
Georgia State University | GSU · Department of Chemistry

Ph.D., Univ. of Pennsylvania

About

102
Publications
16,103
Reads
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Citations
Introduction
Our group is advancing the state-of-the-art in the field of biomolecular modeling to tackle fundamental questions into the mechanisms of DNA replication, genome maintenance, gene regulation and the structures/functions of the large nucleoprotein molecular machines that carry out these processes. This work has direct biomedical relevance, specifically, for the etiology of cancer and inherited genetic disorders. https://ivanov-group.org
Additional affiliations
August 2009 - present
Georgia State University
Position
  • Professor
Description
  • https://ivanov-group.org
January 2005 - May 2009
University of California, San Diego
Position
  • PostDoc Position
August 1999 - December 2004
University of Pennsylvania
Position
  • PhD

Publications

Publications (102)
Article
Full-text available
Transcription-coupled repair is essential for the removal of DNA lesions from the transcribed genome. The pathway is initiated by CSB protein binding to stalled RNA polymerase II. Mutations impairing CSB function cause severe genetic disease. Yet, the ATP-dependent mechanism by which CSB powers RNA polymerase to bypass certain lesions while trigger...
Article
Suboptimal path analysis in a protein structural or dynamical network becomes increasingly popular for identifying critical residues involved in allosteric communication and regulation. Several software packages have been developed for calculating suboptimal paths, including NetworkView, WISP, and CNAPATH (Bio3D). Although these packages work well...
Article
Protein arginine methyltransferases (PRMTs) are essential epigenetic and post-translational regulators in eukaryotic organisms. Dysregulation of PRMTs is intimately related to multiple types of human diseases, particularly cancer. Based on the previously reported PRMT1 inhibitors bearing the diamidine pharmacophore, we performed virtual screening t...
Article
Full-text available
Proofreading by replicative DNA polymerases is a fundamental mechanism ensuring DNA replication fidelity. In proofreading, mis-incorporated nucleotides are excised through the 3′-5′ exonuclease activity of the DNA polymerase holoenzyme. The exonuclease site is distal from the polymerization site, imposing stringent structural and kinetic requiremen...
Article
Full-text available
Critical for transcription initiation and bulky lesion DNA repair, TFIIH provides an exemplary system to connect molecular mechanisms to biological outcomes due to its strong genetic links to different specific human diseases. Recent advances in structural and computational biology provide a unique opportunity to re-examine biologically relevant mo...
Article
Full-text available
DNA replication origins serve as sites of replicative helicase loading. In all eukaryotes, the six-subunit origin recognition complex (Orc1-6; ORC) recognizes the replication origin. During late M-phase of the cell-cycle, Cdc6 binds to ORC and the ORC–Cdc6 complex loads in a multistep reaction and, with the help of Cdt1, the core Mcm2-7 helicase on...
Article
Advances in cryo-electron microscopy (cryo-EM) have revolutionized the structural investigation of large macromolecular assemblies. In this review, we first provide a broad overview of modeling methods used for flexible fitting of molecular models into cryo-EM density maps. We give special attention to approaches rooted in molecular simulations – a...
Article
Full-text available
Transcription preinitiation complexes (PICs) are vital assemblies whose function underlies the expression of protein-encoding genes. Cryo-EM advances have begun to uncover their structural organization. Nevertheless, functional analyses are hindered by incompletely modeled regions. Here we integrate all available cryo-EM data to build a practically...
Article
Sliding clamp proteins encircle duplex DNA and are involved in processive DNA replication and the DNA damage response. Clamp proteins are ring-shaped oligomers (dimers or trimers) and are loaded onto DNA by an ATP-dependent clamp-loader complex that ruptures the interface between two adjacent subunits. Here we measured the solution dynamics of the...
Article
Regulation of gene-expression by specific targeting of protein-nucleic acid interactions has been a long-standing goal in medicinal chemistry. Transcription factors are considered “undruggable” because they lack binding sites well suited for binding small-molecules. In order to overcome this obstacle, we are interested in designing small molecules...
Article
Full-text available
RNA polymerase III (Pol III) transcription initiation requires the action of the transcription factor IIIB (TFIIIB) and is highly regulated. Here, we determine the structures of Pol III pre-initiation complexes (PICs) using single particle cryo-electron microscopy (cryo-EM). We observe stable Pol III–TFIIIB complexes using nucleic acid scaffolds mi...
Article
Full-text available
Thymine DNA glycosylase (TDG) is a pivotal enzyme with dual roles in both genome maintenance and epigenetic regulation. TDG is involved in cytosine demethylation at CpG sites in DNA. Here we have used molecular modeling to delineate the lesion search and DNA base interrogation mechanisms of TDG. First, we examined the capacity of TDG to interrogate...
Article
Full-text available
Metabolic reprogramming of cancer cells is essential for tumorigenesis, in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C42...
Article
Full-text available
Transcription initiation by RNA Polymerase I (Pol I) depends on the Core Factor (CF) complex to recognize the upstream promoter and assemble into a Pre-Initiation Complex (PIC). Here, we solve a structure of Saccharomyces cerevisiae Pol I-CF-DNA to 3.8Å resolution using single-particle cryo-electron microscopy. The structure reveals a bipartite arc...
Article
Full-text available
Human flap endonuclease 1 (FEN1) and related structure-specific 5’nucleases precisely identify and incise aberrant DNA structures during replication, repair and recombination to avoid genomic instability. Yet, it is unclear how the 5’nuclease mechanisms of DNA distortion and protein ordering robustly mediate efficient and accurate substrate recogni...
Article
Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series...
Article
Full-text available
Specific targeting of protein–nucleic acid interactions is an area of current interest, for example, in the regulation of gene-expression. Most transcription factor proteins bind in the DNA major groove; however, we are interested in an approach using small molecules to target the minor groove to control expression by an allosteric mechanism. In an...
Article
Full-text available
Integrin αν β3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αν β3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αν β3 -expressing cells by recruiting a...
Data
Supplementary Figures 1-11 and Supplementary Tables 1-2
Article
Full-text available
Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally veri...
Article
Full-text available
In eukaryotic transcription initiation, a large multi-subunit pre-initiation complex (PIC) that assembles at the core promoter is required for the opening of the duplex DNA and identification of the start site for transcription by RNA polymerase II. Here we use cryo-electron microscropy (cryo-EM) to determine near-atomic resolution structures of th...
Data
Densities are shown as a semi-transparent surface following a similar colour scheme to that in the main section. A region corresponding to the double-psi beta-barrel domain composing the conserved core of Pol II within Rpb1 and Rpb2 is shown as an example of near-atomic resolution features. Colour scheme for the promoter DNA is shown at the bottom.
Data
By aligning the three models of holo-PICs (CC, OC, and ITC) using the rigid part of Pol II, sequential states are morphed with a special focus on the nucleic acids regions.
Data
Densities are shown as a semi-transparent surface following a similar colour scheme to that in the main section. A region corresponding to the active site of Pol II is shown as an example of near-atomic resolution features. Color scheme for the promoter DNA is shown at the bottom.
Article
Full-text available
Replicative DNA polymerases (Pols) frequently possess two distinct DNA processing activities - DNA synthesis (polymerization) and proofreading (3'-5' exonuclease activity). The polymerase and exonuclease reactions are performed alternately and are spatially separated in different protein domains. Thus, the growing DNA primer terminus has to undergo...
Data
PolB domains are colored as follows: N-terminal domain in light blue; exonuclease domain in green; palm domain in cyan; fingers domain in gold and thumb domain in red. PCNA and DNA are shown in grey and black.
Data
PolB domains are colored as follows: N-terminal domain in light blue; exonuclease domain in green; palm domain in cyan; fingers domain in gold and thumb domain in red. PCNA and DNA are shown in grey and black. The hinge region is highlighted in yellow.
Data
Contact residues are explicitly shown in ball and stick representation. Contact types are colored as follows: Salt-bridges in light blue and red; persistent hydrogen bonds (other than salt bridges) in cyan and dark blue; hydrophobic interaction in green and purple.
Data
Contact residues are explicitly shown in ball and stick representation. Contact types are colored as follows: Salt-bridges in light blue and red; persistent hydrogen bonds (other than salt bridges) in cyan and dark blue; hydrophobic interaction in green and purple.
Data
PolB domains are colored as follows: N-terminal domain in light blue; exonuclease domain in green; palm domain in cyan; fingers domain in gold; and thumb domain in red. PCNA is shown in grey. The path is qualitatively similar to the targeted MD trajectory and is comprised primarily of the two lowest normal modes.
Article
Full-text available
Many genomes contain families of paralogs—proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and...
Article
Full-text available
Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog 1 (LRH 1), which has evolved a novel allosteric pathway to support appropriate interaction with coregulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for...
Article
Full-text available
Small angle X-ray scattering (SAXS) Electron microscopy (EM) DNA replication and repair While conventional high-resolution techniques in structural biology are challenged by the size and flexibility of many biological assemblies, recent advances in low-resolution techniques such as cryo-electron microscopy (cryo-EM) and small angle X-ray scattering...
Conference Paper
Full-text available
Cancer cells have altered metabolic functions and significantly increased energy demands required to maintain and support rapid cell proliferation. In addition, metastatic tumor cells need an abundance of phosphometabolites that are used to synthesize the components needed for cellular proliferation, all while enduring potentially unfavorable condi...
Article
Full-text available
Replication Protein A (RPA) is an essential scaffold for many DNA processing machines; its function relies on its modular architecture. Here, we report (15)N-nuclear magnetic resonance heteronuclear relaxation analysis to characterize the movements of single-stranded (ss) DNA binding and protein interaction modules in the RPA70 subunit. Our results...
Article
Full-text available
Proliferating cell nuclear antigen (PCNA) is a pivotal replication protein, which also controls cellular responses to DNA damage. Posttranslational modification of PCNA by SUMO and ubiquitin modulate these responses. How the modifiers alter PCNA-dependent DNA repair and damage tolerance pathways is largely unknown. We used hybrid methods to identif...
Article
Full-text available
Author Summary DNA repair efficiency is critically dependent on the function of DNA glycosylases. These versatile enzymes perform a remarkably discriminating search for DNA lesions, followed by damage-specific base extrusion into to the enzyme's active site and removal of the damaged bases. Our work elucidates the mechanism of Bacillus cereus AlkD,...
Article
Full-text available
Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) have been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targeting many methyltransferase en...
Article
Flap endonuclease 1 (FEN1) and XPG are essential 5′ nuclease superfamily endonucleases in DNA replication and repair. FEN1 incises in the dsDNA region adjacent to 5′ flaps, while XPG incises in the dsDNA region adjacent to DNA bubbles. We have used a hybrids method analysis combining crystallography, Small Angle X-ray Scattering (SAXS), Electron Mi...
Article
The bacterial recombinase RecA mediates homologous recombination and recombinational DNA repair through homology search and strand exchange. During homologous recombination, RecA binds an incoming single-stranded DNA (ssDNA) in its primary binding site, site I, to form a nucleoprotein filament whose crystal structure is known. The structure of the...
Article
Full-text available
Proliferating cell nuclear antigen and the checkpoint clamp Rad9-Rad1-Hus1 topologically encircle DNA and act as mobile platforms in the recruitment of proteins involved in DNA damage response and cell cycle regulation. To fulfill these vital cellular functions, both clamps need to be opened and loaded onto DNA by a clamp loader complex—a process,...
Article
Full-text available
Detailed mechanisms of DNA clamps in prokaryotic and eukaryotic systems were investigated by probing their mechanics with single-molecule force spectroscopy. Specifically, the mechanical forces required for the Escherichia coli and Saccharomyces cerevisiae clamp opening were measured at the single-molecule level by optical tweezers. Steered molecul...
Article
Full-text available
Non-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair, AP sites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease fa...
Article
Full-text available
By coupling the protection and organization of single-stranded DNA (ssDNA) with recruitment and alignment of DNA processing factors, replication protein A (RPA) lies at the heart of dynamic multi-protein DNA processing machinery. Nevertheless, how RPA coordinates biochemical functions of its eight domains remains unknown. We examined the structural...
Article
Full-text available
The metal cofactors responsible for the activity of CDK2 -- a representative member of the kinase superfamily of enzymes -- have now been shown to also have inhibitory effects during the catalytic cycle.