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Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 3803

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Special Issue Editor

Dr. Brad C. Bennett

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Biological and Environmental Science Department, Howard College of Arts and Sciences, Samford University, Birmingham, AL 35229, USA
Interests: structural biology; antibiotic drug design; human membrane proteins; probiotic metabolites; molecular microbiology; microbial evolution
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Special Issue Information

Dear Colleagues,

Like you, I was surprised and saddened by the untimely death of Dr. Chris Dealwis, Associate Professor of Pharmacology at Case Western Reserve University (CWRU), in July 2022. He was my Ph.D. mentor, and I continued to collaborate with him until his death. Chris pursued high-resolution structural biology and worked on several important macromolecular structures, including renin, chemokines, amyloid-recognizing antibodies, ribonucleotide reductase, and dihydrofolate reductase. He was especially interested in and talented at applying a plethora of structural methods, including X-ray and neutron crystallography, mass spectrometry, and fluorescence spectroscopy, among others, to probe complex biological assemblies, inform drug design strategies, and address fundamental biochemical problems.

We are pleased to invite you to contribute an article to a special memorial issue that will serve to celebrate Chris’s scientific life and work.

This Special Issue aims to highlight all manner of biochemical and biophysical methods, such as the ones listed above, that are used to elucidate the macromolecular structure and/or evaluate protein targets for drug design efforts. This appreciation and blend of disparate methods to answer important biological questions reflect Chris’s successful scientific career.

Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: Structural Biology, Medicinal Chemistry, Pharmacology, Molecular Biology, Biochemistry, Biophysical Chemistry, and methods developed for any of the areas listed here. Additionally, any reflections on Chris and his work may be included in your article if appropriate.

Thank you for your consideration, and I look forward to receiving your contributions.

Dr. Brad C. Bennett
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

structural biology
crystallography
spectroscopy
neutron diffraction
enzyme mechanism
drug design
cancer chemotherapy
protein dynamics
electron microscopy

Published Papers (3 papers)

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Research

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14 pages, 2732 KiB

Open AccessArticle

Novel Covalent Modifier-Induced Local Conformational Changes within the Intrinsically Disordered Region of the Androgen Receptor

by Michael T. Harnish, Daniel Lopez, Corbin T. Morrison, Ramesh Narayanan, Elias J. Fernandez and Tongye Shen

Biology 2023, 12(11), 1442; https://doi.org/10.3390/biology12111442 - 17 Nov 2023

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Abstract

Intrinsically disordered regions (IDRs) of transcription factors play an important biological role in liquid condensate formation and gene regulation. It is thus desirable to investigate the druggability of IDRs and how small-molecule binders can alter their conformational stability. For the androgen receptor (AR), certain covalent ligands induce important changes, such as the neutralization of the condensate. To understand the specificity of ligand–IDR interaction and potential implications for the mechanism of neutralizing liquid–liquid phase separation (LLPS), we modeled and performed computer simulations of ligand-bound peptide segments obtained from the human AR. We analyzed how different covalent ligands affect local secondary structure, protein contact map, and protein–ligand contacts for these protein systems. We find that effective neutralizers make specific interactions (such as those between cyanopyrazole and tryptophan) that alter the helical propensity of the peptide segments. These findings on the mechanism of action can be useful for designing molecules that influence IDR structure and condensate of the AR in the future. Full article

(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)

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Review

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32 pages, 8389 KiB

Open AccessReview

Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures

by Maciej Jagielnicki, Iga Kucharska, Brad C. Bennett, Andrew L. Harris and Mark Yeager

Biology 2024, 13(5), 298; https://doi.org/10.3390/biology13050298 - 26 Apr 2024

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Abstract

Connexins (Cxs) are a family of integral membrane proteins, which function as both hexameric hemichannels (HCs) and dodecameric gap junction channels (GJCs), behaving as conduits for the electrical and molecular communication between cells and between cells and the extracellular environment, respectively. Their proper functioning is crucial for many processes, including development, physiology, and response to disease and trauma. Abnormal GJC and HC communication can lead to numerous pathological states including inflammation, skin diseases, deafness, nervous system disorders, and cardiac arrhythmias. Over the last 15 years, high-resolution X-ray and electron cryomicroscopy (cryoEM) structures for seven Cx isoforms have revealed conservation in the four-helix transmembrane (TM) bundle of each subunit; an αβ fold in the disulfide-bonded extracellular loops and inter-subunit hydrogen bonding across the extracellular gap that mediates end-to-end docking to form a tight seal between hexamers in the GJC. Tissue injury is associated with cellular Ca²⁺ overload. Surprisingly, the binding of 12 Ca²⁺ ions in the Cx26 GJC results in a novel electrostatic gating mechanism that blocks cation permeation. In contrast, acidic pH during tissue injury elicits association of the N-terminal (NT) domains that sterically blocks the pore in a “ball-and-chain” fashion. The NT domains under physiologic conditions display multiple conformational states, stabilized by protein–protein and protein–lipid interactions, which may relate to gating mechanisms. The cryoEM maps also revealed putative lipid densities within the pore, intercalated among transmembrane α-helices and between protomers, the functions of which are unknown. For the future, time-resolved cryoEM of isolated Cx channels as well as cryotomography of GJCs and HCs in cells and tissues will yield a deeper insight into the mechanisms for channel regulation. The cytoplasmic loop (CL) and C-terminal (CT) domains are divergent in sequence and length, are likely involved in channel regulation, but are not visualized in the high-resolution X-ray and cryoEM maps presumably due to conformational flexibility. We expect that the integrated use of synergistic physicochemical, spectroscopic, biophysical, and computational methods will reveal conformational dynamics relevant to functional states. We anticipate that such a wealth of results under different pathologic conditions will accelerate drug discovery related to Cx channel modulation. Full article

(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)

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19 pages, 3926 KiB

Open AccessReview

Significance of Histidine Hydrogen–Deuterium Exchange Mass Spectrometry in Protein Structural Biology

by Masaru Miyagi and Takashi Nakazawa

Biology 2024, 13(1), 37; https://doi.org/10.3390/biology13010037 - 9 Jan 2024

Viewed by 1477

Abstract

Histidine residues play crucial roles in shaping the function and structure of proteins due to their unique ability to act as both acids and bases. In other words, they can serve as proton donors and acceptors at physiological pH. This exceptional property is attributed to the side-chain imidazole ring of histidine residues. Consequently, determining the acid-base dissociation constant (Ka) of histidine imidazole rings in proteins often yields valuable insights into protein functions. Significant efforts have been dedicated to measuring the pKa values of histidine residues in various proteins, with nuclear magnetic resonance (NMR) spectroscopy being the most commonly used technique. However, NMR-based methods encounter challenges in assigning signals to individual imidazole rings and require a substantial amount of proteins. To address these issues associated with NMR-based approaches, a mass-spectrometry-based method known as histidine hydrogen–deuterium exchange mass spectrometry (His-HDX-MS) has been developed. This technique not only determines the pKa values of histidine imidazole groups but also quantifies their solvent accessibility. His-HDX-MS has proven effective across diverse proteins, showcasing its utility. This review aims to clarify the fundamental principles of His-HDX-MS, detail the experimental workflow, explain data analysis procedures and provide guidance for interpreting the obtained results. Full article

(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)

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