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Characterization Of Human Pyrroline-5-Carboxylate Reductase Enzymes Responsible For L-Proline Biosynthesis, Sagar Patel 2020 University of Nebraska - Lincoln

Characterization Of Human Pyrroline-5-Carboxylate Reductase Enzymes Responsible For L-Proline Biosynthesis, Sagar Patel

Theses and Dissertations in Biochemistry

Pyrroline-5-carboxylate reductases (EC 1.5.1.2) are important housekeeping enzymes of L-proline biosynthesis, which generate L-proline and influence redox cycling of NAD(P)H/NAD(P)+ to support cellular growth in all domains of life. Structural evidence from X-ray crystal structures of HsPYCR1 (PDB codes 5UAT, 5UAU, and 5UAV) shows both NADPH bound in the N-terminal Rao-Rossmann fold motif and an important hydrogen bond or proton donor role for Thr238 with L-P5C. The Thr238Ala mutation results in 10-fold loss in catalytic efficiency with varied L-P5C relative to the wild-type enzyme, thus indicating Thr238’s potential hydrogen bond and proton ...


Structural Analysis Of Potent Hybrid Hiv-1 Protease Inhibitors Containing Bis-Tetrahydrofuran In A Pseudo-Symmetric Dipeptide Isostere, Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali 2020 University of Massachusetts Medical School

Structural Analysis Of Potent Hybrid Hiv-1 Protease Inhibitors Containing Bis-Tetrahydrofuran In A Pseudo-Symmetric Dipeptide Isostere, Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali

University of Massachusetts Medical School Faculty Publications

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the ...


Deciphering Complex Mechanisms Of Resistance And Loss Of Potency Through Coupled Molecular Dynamics And Machine Learning, Florian Leidner, Nese Kurt Yilmaz, Celia A. Schiffer 2020 University of Massachusetts Medical School

Deciphering Complex Mechanisms Of Resistance And Loss Of Potency Through Coupled Molecular Dynamics And Machine Learning, Florian Leidner, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Drug resistance threatens many critical therapeutics through mutations in the drug target. The molecular mechanisms by which combinations of mutations, especially involving those distal from the active site, alter drug binding to confer resistance are poorly understood and thus difficult to counteract. A strategy coupling parallel molecular dynamics simulations and machine learning to identify conserved mechanisms underlying resistance was developed. A series of 28 HIV-1 protease variants with up to 24 varied substitutions were used as a rigorous model of this strategy. Many of the mutations were distal from the active site and the potency to darunavir varied from low ...


Dynamics Of The 4d Genome During In Vivo Lineage Specification And Differentiation, A. Marieke Oudelaar, Daniel Hidalgo, Merav Socolovsky, Douglas R. Higgs, Jim R. Hughes 2020 University of Oxford

Dynamics Of The 4d Genome During In Vivo Lineage Specification And Differentiation, A. Marieke Oudelaar, Daniel Hidalgo, Merav Socolovsky, Douglas R. Higgs, Jim R. Hughes

Open Access Articles

Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of ...


Mrna Stem-Loops Can Pause The Ribosome By Hindering A-Site Trna Binding, Chen Bao, Sarah Loerch, Clarence Ling, Andrei A. Korostelev, Nikolaus Grigorieff, Dmitri N. Ermolenko 2020 University of Rochester

Mrna Stem-Loops Can Pause The Ribosome By Hindering A-Site Trna Binding, Chen Bao, Sarah Loerch, Clarence Ling, Andrei A. Korostelev, Nikolaus Grigorieff, Dmitri N. Ermolenko

Open Access Articles

Although the elongating ribosome is an efficient helicase, certain mRNA stem-loop structures are known to impede ribosome movement along mRNA and stimulate programmed ribosome frameshifting via mechanisms that are not well understood. Using biochemical and single-molecule Forster resonance energy transfer (smFRET) experiments, we studied how frameshift-inducing stem-loops from E. coli dnaX mRNA and the gag-pol transcript of Human Immunodeficiency Virus (HIV) perturb translation elongation. We find that upon encountering the ribosome, the stem-loops strongly inhibit A-site tRNA binding and ribosome intersubunit rotation that accompanies translation elongation. Electron cryo-microscopy (cryo-EM) reveals that the HIV stem-loop docks into the A site of ...


Intrinsic Buffer Hydroxyl Radical Dosimetry For Hydroxyl Radical Protein Footprinting, Addison Roush 2020 University of Mississippi

Intrinsic Buffer Hydroxyl Radical Dosimetry For Hydroxyl Radical Protein Footprinting, Addison Roush

Honors Theses

Hydroxyl radical protein footprinting (HRPF) coupled to mass spectrometry is a powerful technique for the analysis of protein topography as it generates covalent mass labels that can survive downstream sample handling, and it is sensitive to the solvent accessibility of amino acid sidechains. Of the multiple platforms for HRPF, fast photochemical oxidation of proteins (FPOP) utilizes a pulsed 248 nm KrF excimer laser to label proteins by photolyzing hydrogen peroxide. FPOP is the most widely used HRPF platform because it labels proteins faster than unfolding can occur. Variations in FPOP sample conditions make it difficult to compare results between experiments ...


Titus Thesis Figures.Docx, Titus Hou 2020 University of Iowa

Titus Thesis Figures.Docx, Titus Hou

Titus Hou

No abstract provided.


Titus Thesis.Docx, Titus Hou 2020 University of Iowa

Titus Thesis.Docx, Titus Hou

Titus Hou

No abstract provided.


Characterizing The Long-Range And Short-Range Interactions Stabilizing A Model Sh3 Recognition Complex, Colin McClure 2020 Skidmore College

Characterizing The Long-Range And Short-Range Interactions Stabilizing A Model Sh3 Recognition Complex, Colin Mcclure

Chemistry Senior Theses

SH3 domains are common recognition domains found in many protein complexes of all eukaryotes. Their regulatory functions are involved in cell proliferation, differentiation, cytoskeleton modification and are vital for cellular communication. We have used Molecular Dynamics (MD) simulations to computationally model a common interaction between the AbpSH3 domain and the intrinsically disordered peptide, ArkA. This work is in collaboration with and in support of previous experimental studies of the complex aimed to characterize the binding pathway including NMR, ITC, and chemical denaturation. Specifically, my work focuses on the long-range electrostatic interactions involved in stabilizing the bound AbpSH3- ArkA complex. Previous ...


Cloning And Expression Of Hydra Innexin 2, A Gap Junction Protein Required For Coordinated Contraction Of The Body Column, Ashley O'Brien 2020 Buffalo State College

Cloning And Expression Of Hydra Innexin 2, A Gap Junction Protein Required For Coordinated Contraction Of The Body Column, Ashley O'Brien

Biology Theses

In invertebrates gap junctions are formed by the innexin family of proteins. Remarkably, the genome of Hydra magnipapillata contains 17 innexin genes. This study focused on Hydra innexin-2 (h-Inx2) which is expressed in nerve cells and plays a role in contraction of the body column. The gene sequence of H-Inx2 was obtained from the National Center for Biotechnology Information (NCBI), the gene was synthesized externally and transferred to a vector suitable for expression in Xenopus oocytes (pcDNA3.1 CT-GFP TOPO). The TOPO CT-GFP vector includes a priming site for RNA polymerase which allows in vitro preparation of RNA. Another advantage ...


Pedagogical Approaches To Enhance Q2s Conversion Teaching And Learning: Application Of The Acue Effective Practice Framework To Upper Division Biochemistry, Jason Burke 2020 California State University, San Bernardino

Pedagogical Approaches To Enhance Q2s Conversion Teaching And Learning: Application Of The Acue Effective Practice Framework To Upper Division Biochemistry, Jason Burke

Q2S Enhancing Pedagogy

The Effective Practice Framework course by the Association of College and University Educators (ACUE), and offered through the CSUSB Teaching Resource Center (TRC), was applied to the upper division biochemistry course series (CHEM 436A and 437A) in preparation for the Q2S conversion. This essay includes five reflections on the application of enhanced pedagogical approaches curated from a total of twenty-five. The enhanced pedagogies covered in the course are: designing and effective course and class; establishing a productive learning environment; using active learning techniques; promoting higher-order thinking; and assessing to inform instruction and promote learning. The reflections that follow have been ...


Functional Analysis Of A Critical Glycine (Glycine 12) In Beta-Type Connexins Of Human Skin, Rasheed Bailey 2020 State University of New York College at Buffalo - Buffalo State College

Functional Analysis Of A Critical Glycine (Glycine 12) In Beta-Type Connexins Of Human Skin, Rasheed Bailey

Biology Theses

At least five beta-type connexins are expressed in various layers of the skin (Cx26, Cx30, Cx30.3, Cx31, and Cx32) and all include a glycine residue at position 12. Glycine12 (G12) is located about halfway through the cytoplasmic amino terminus and has been the focus of several studies related to connexin diseases and gap junction channel structure. The importance of this residue is evident in the severity and diversity of diseases associated with amino acid substitutions at G12 including hereditary forms of skin disease, deafness and neuropathy. This study uses bioinformatic analysis in combination with mutational analysis and electrophysiology to ...


470— Quantifying The Shape Of A Plant (Brassica Rapa) During Growth Under Different Light Intensities Using Fractal Geometry, Matthew Cotroneo 2020 SUNY Geneseo

470— Quantifying The Shape Of A Plant (Brassica Rapa) During Growth Under Different Light Intensities Using Fractal Geometry, Matthew Cotroneo

GREAT Day

Over time plants not only increase in size but also change their shape. Quantifying this change in shape, however, is challenging. Fractal dimension, a measure of how these plants fill space, can provide a wholistic understanding of plant shape and how that shape changes as the plants react to their environments. I used a high-resolution, three-dimensional scanner to estimate the shape of Brassica rapa plants during growth under three different light intensities: low (40 Einsteins), medium (75 Einsteins) and high (100 Einsteins). From these data, each plant's above-ground shape was quantified using fractal geometry. The fractal dimension (D) of ...


Structure Of The Human Clamp Loader Bound To The Sliding Clamp: A Further Twist On Aaa+ Mechanism, Christl Gaubitz, Xingchen Liu, Joseph Magrino, Nicholas P. Stone, Jacob Landeck, Mark Hedglin, Brian A. Kelch 2020 University of Massachusetts Medical School

Structure Of The Human Clamp Loader Bound To The Sliding Clamp: A Further Twist On Aaa+ Mechanism, Christl Gaubitz, Xingchen Liu, Joseph Magrino, Nicholas P. Stone, Jacob Landeck, Mark Hedglin, Brian A. Kelch

University of Massachusetts Medical School Faculty Publications

DNA replication requires the sliding clamp, a ring-shaped protein complex that encircles DNA, where it acts as an essential cofactor for DNA polymerases and other proteins. The sliding clamp needs to be actively opened and installed onto DNA by a clamp loader ATPase of the AAA+ family. The human clamp loader Replication Factor C (RFC) and sliding clamp PCNA are both essential and play critical roles in several diseases. Despite decades of study, no structure of human RFC has been resolved. Here, we report the structure of human RFC bound to PCNA by cryo-EM to an overall resolution of ~3 ...


The Role Of Conformational Dynamics In Isocyanide Hydratase Catalysis, Medhanjali Dasgupta 2020 University of Nebraska - Lincoln

The Role Of Conformational Dynamics In Isocyanide Hydratase Catalysis, Medhanjali Dasgupta

Theses and Dissertations in Biochemistry

Post-translational modification of cysteine residues can regulate protein function and is essential for catalysis by cysteine-dependent enzymes. Covalent modifications neutralize charge on the reactive cysteine thiolate anion and thus alter the active site electrostatic environment. Although a vast number of enzymes rely on cysteine modification for function, precisely how altered structural and electrostatic states of cysteine affect protein dynamics, which in turn, affects catalysis, remains poorly understood.

Here we use X-ray crystallography, computer simulations, site directed mutagenesis and enzyme kinetics to characterize how covalent modification of the active site cysteine residue in the enzyme, isocyanide hydratase (ICH), affects the protein ...


Clostridium Perfringens Adhesion Through Type Iv Pili, Alexander Meyer, Josephine Liess, Kurt Piepenbrink 2020 University of Nebraska-Lincoln

Clostridium Perfringens Adhesion Through Type Iv Pili, Alexander Meyer, Josephine Liess, Kurt Piepenbrink

UCARE Research Products

Bacteria infect host cells through several mechanisms, one of which is a surface protein called a type IV pilus. Type IV pili are thin, hair-like protein fibers on the bacterial surface capable of being extended and retracted from a bacterial cell; they are used for functions including motility, biofilm formation, and adherence to host cells. Clostridium perfringens is a Gram-positive bacterium best known as a food pathogen that is believed to use type IV pili for host cell adherence. These pili are poorly characterized and understanding how C. perfringens uses type IV pili will provide a model for how these ...


Cryoem Structure Of Ctbp2 Confirms Tetrameric Architecture, Anne M. Jecrois, M. Michael Dcona, Xiaovan Deng, Dipankar Bandyopadhyay, Steven R. Grossman, Celia A. Schiffer, William E. Royer 2020 University of Massachusetts Medical School

Cryoem Structure Of Ctbp2 Confirms Tetrameric Architecture, Anne M. Jecrois, M. Michael Dcona, Xiaovan Deng, Dipankar Bandyopadhyay, Steven R. Grossman, Celia A. Schiffer, William E. Royer

University of Massachusetts Medical School Faculty Publications

C-terminal binding proteins 1 and 2 (CtBP1 and CtBP2) are transcriptional regulators that activate or repress many genes involved in cellular development, apoptosis and metastasis. CtBP proteins are activated under hypoxic conditions where NAD(H) levels tend to be higher. NADH-dependent activation of CtBP2 has direct implication in multiple types of cancers and poor patient prognosis. Previous studies have proposed dimeric CtBP as the relevant oligomeric state, however our studies with multi-angle light scattering have shown that the primary effect of NADH binding is to promote the assembly of two CtBP dimers into tetramers. Here, we present the cryoEM structures ...


Cylindrical Similarity Measurement For Helices In Medium-Resolution Cryo-Electron Microscopy Density Maps, Salim Sazzed, Peter Scheible, Maytha Alshammari, Willy Wriggers, Jing He 2020 Old Dominion University

Cylindrical Similarity Measurement For Helices In Medium-Resolution Cryo-Electron Microscopy Density Maps, Salim Sazzed, Peter Scheible, Maytha Alshammari, Willy Wriggers, Jing He

College of Sciences Posters

Cryo-electron microscopy (cryo-EM) density maps at medium resolution (5-10 Å) reveal secondary structural features such as α-helices and β-sheets, but they lack the side chains details that would enable a direct structure determination. Among the more than 800 entries in the Electron Microscopy Data Bank (EMDB) of medium-resolution density maps that are associated with atomic models, a wide variety of similarities can be observed between maps and models. To validate such atomic models and to classify structural features, a local similarity criterion, the F1 score, is proposed and evaluated in this study. The F1 score is theoretically normalized to a ...


Avoiding Drug Resistance By Substrate Envelope-Guided Design: Toward Potent And Robust Hcv Ns3/4a Protease Inhibitors, Ashley N. Matthew, Jacqueto Zephyr, Nageswara Rao Desaboini, Mina Henes, Wasih Kamran, Klajdi Kosovrasti, Adam Hedger, Gordon J. Lockbaum, Jennifer Timm, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer 2020 University of Massachusetts Medical School

Avoiding Drug Resistance By Substrate Envelope-Guided Design: Toward Potent And Robust Hcv Ns3/4a Protease Inhibitors, Ashley N. Matthew, Jacqueto Zephyr, Nageswara Rao Desaboini, Mina Henes, Wasih Kamran, Klajdi Kosovrasti, Adam Hedger, Gordon J. Lockbaum, Jennifer Timm, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility ...


Detecting Chromatin Interactions Along And Between Sister Chromatids With Sisterc, Marlies E. Oomen, Adam K. Hedger, Jonathan K. Watts, Job Dekker 2020 University of Massachusetts Medical School

Detecting Chromatin Interactions Along And Between Sister Chromatids With Sisterc, Marlies E. Oomen, Adam K. Hedger, Jonathan K. Watts, Job Dekker

University of Massachusetts Medical School Faculty Publications

Accurate chromosome segregation requires chromosome compaction with concordant disentanglement of the two sister chromatids. This process has been studied extensively by microscopy but has remained a challenge for genomic methods, such as Hi-C, because sister chromatids have identical DNA sequences. Here we describe SisterC, a chromosome conformation capture assay that can distinguish interactions between and within sister chromatids. The assay is based on BrdU incorporation during S-phase, which labels the newly replicated strands of the sister chromatids. This is followed by Hi-C, e.g. during different stages of mitosis, and the selective destruction of BrdU containing strands by UV/Hoechst ...


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