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Emerging Topics in Protein Crystallography
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Emerging Topics in Protein Crystallography

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 6045

Special Issue Editors

Prof. Dr. Giuseppe Zanotti

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
Interests: structural biology; protein crystallography; cryo-electron microscopy; bacterial proteins; Helicobacter pylori; transport proteins
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Zhongzhou Chen

E-Mail Website
Guest Editor
State Key Laboratory of Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing 100193, China
Interests: structural biology; cancers; epigenetics; demethylation; transcription regulation; viral polymerase; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the determination of the first 3D crystal structure of myoglobin in 1958, protein crystallography has developed into a mature structural biology technique, solving ~87% of the structures deposited in the Protein Data Bank (PDB). Moreover, in the last few years, two events have revolutionized the field of structural biology: the “resolution revolution” of cryo-electron microscopy (cryo-EM), which allows the visualization of single particles at a near-atomic resolution without the need of growing them in a crystalline form, and the recent development of AlphaFold 2, an A.I. system able to predict the 3D structure of a single protein with high reliability. This last event will strongly influence crystallography, since most of the future crystal structures will be solved using the molecular replacement technique. In parallel, new techniques/methods are emerging in crystallography, such as new crystal growing methods, more intense and focused X-ray beams, novel data collection methods, ultra-sensitive detectors, advanced computational algorithms, and new software.

It is easy to foresee that in the next few years, the application of these techniques will revolutionize our understanding of the molecular mechanisms of cell biology, with a wide impact spanning across biochemistry, life science, and medicine. The present Special Issue aims to summarize frontier technologies and methodological advances in the field, as well as the structures and functions of special proteins or protein complexes; to take stock of the present situation; and to create a virtual forum for the future of Structural Biology.

Prof. Dr. Giuseppe Zanotti
Prof. Dr. Zhongzhou Chen
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • protein crystallography
  • structural biology
  • high-throughput crystallography
  • cryo-EM
  • NMR
  • radiation sources
  • X-ray detectors
  • structure determination
  • molecular mechanism
  • functions
  • drug discovery

Related Special Issue

Published Papers (5 papers)

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Research

19 pages, 5834 KiB  
Article
Structural Basis of Nucleic Acid Recognition and 6mA Demethylation by Caenorhabditis elegans NMAD-1A
by Guohui Shang, Meiting Yang, Min Li, Lulu Ma, Yunlong Liu, Jun Ma, Yiyun Chen, Xue Wang, Shilong Fan, Mengjia Xie, Wei Wu, Shaodong Dai and Zhongzhou Chen
Int. J. Mol. Sci. 2024, 25(2), 686; https://doi.org/10.3390/ijms25020686 - 05 Jan 2024
Viewed by 996
Abstract
N6-methyladenine (6mA) of DNA is an emerging epigenetic mark in the genomes of Chlamydomonas, Caenorhabditis elegans, and mammals recently. Levels of 6mA undergo drastic fluctuation and thus affect fertility during meiosis and early embryogenesis. Here, we showed three complex [...] Read more.
N6-methyladenine (6mA) of DNA is an emerging epigenetic mark in the genomes of Chlamydomonas, Caenorhabditis elegans, and mammals recently. Levels of 6mA undergo drastic fluctuation and thus affect fertility during meiosis and early embryogenesis. Here, we showed three complex structures of 6mA demethylase C. elegans NMAD-1A, a canonical isoform of NMAD-1 (F09F7.7). Biochemical results revealed that NMAD-1A prefers 6mA Bubble or Bulge DNAs. Structural studies of NMAD-1A revealed an unexpected “stretch-out” conformation of its Flip2 region, a conserved element that is usually bent over the catalytic center to facilitate substrate base flipping in other DNA demethylases. Moreover, the wide channel between the Flip1 and Flip2 of the NMAD-1A explained the observed preference of NMAD-1A for unpairing substrates, of which the flipped 6mA was primed for catalysis. Structural analysis and mutagenesis studies confirmed that key elements such as carboxy-terminal domain (CTD) and hypothetical zinc finger domain (ZFD) critically contributed to structural integrity, catalytic activity, and nucleosome binding. Collectively, our biochemical and structural studies suggest that NMAD-1A prefers to regulate 6mA in the unpairing regions and is thus possibly associated with dynamic chromosome regulation and meiosis regulation. Full article
(This article belongs to the Special Issue Emerging Topics in Protein Crystallography)
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10 pages, 4635 KiB  
Communication
Structural Characterization of an N-Acetyl Sugar Amidotransferase Involved in the Lipopolysaccharide Biosynthesis in Bacteria
by Jiajia Gao, Wenwen Xu, Tianqi Liu, Wenjie Sun, Na Wang, Jinming Ma and Honghua Ge
Int. J. Mol. Sci. 2023, 24(20), 15491; https://doi.org/10.3390/ijms242015491 - 23 Oct 2023
Viewed by 824
Abstract
N-acetyl sugar amidotransferase (NASAT) is involved in the lipopolysaccharide (LPS) biosynthesis pathway that catalyzes the formation of the acetamido moiety (sugar-NC(=NH)CH3) on the O-chain. So far, little is known about its structural and functional properties. Here, we report the crystal structure of an [...] Read more.
N-acetyl sugar amidotransferase (NASAT) is involved in the lipopolysaccharide (LPS) biosynthesis pathway that catalyzes the formation of the acetamido moiety (sugar-NC(=NH)CH3) on the O-chain. So far, little is known about its structural and functional properties. Here, we report the crystal structure of an N-acetyl sugar amidotransferase from Legionella pneumophila (LpNASAT) at 2.33 Å resolution. LpNASAT folds into a compact basin-shaped architecture with an unusually wide and open putative substrate-binding pocket and a conserved zinc ion-binding tetracysteine motif. The pocket contains a Rossmann-like fold with a PP-loop, suggesting that the NASAT-catalyzed amidotransfer reaction probably requires the conversion of ATP to AMP and PPi. Our data provide structural insights into the NASAT family of proteins, and allow us to possibly identify its functionally important regions. Full article
(This article belongs to the Special Issue Emerging Topics in Protein Crystallography)
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13 pages, 6590 KiB  
Article
High-Confidence Placement of Fragments into Electron Density Using Anomalous Diffraction—A Case Study Using Hits Targeting SARS-CoV-2 Non-Structural Protein 1
by Shumeng Ma, Vitaliy Mykhaylyk, Matthew W. Bowler, Nikos Pinotsis and Frank Kozielski
Int. J. Mol. Sci. 2023, 24(13), 11197; https://doi.org/10.3390/ijms241311197 - 07 Jul 2023
Cited by 2 | Viewed by 1296
Abstract
The identification of multiple simultaneous orientations of small molecule inhibitors binding to a protein target is a common challenge. It has recently been reported that the conformational heterogeneity of ligands is widely underreported in the Protein Data Bank, which is likely to impede [...] Read more.
The identification of multiple simultaneous orientations of small molecule inhibitors binding to a protein target is a common challenge. It has recently been reported that the conformational heterogeneity of ligands is widely underreported in the Protein Data Bank, which is likely to impede optimal exploitation to improve affinity of these ligands. Significantly less is even known about multiple binding orientations for fragments (<300 Da), although this information would be essential for subsequent fragment optimisation using growing, linking or merging and rational structure-based design. Here, we use recently reported fragment hits for the SARS-CoV-2 non-structural protein 1 (nsp1) N-terminal domain to propose a general procedure for unambiguously identifying binding orientations of 2-dimensional fragments containing either sulphur or chloro substituents within the wavelength range of most tunable beamlines. By measuring datasets at two energies, using a tunable beamline operating in vacuum and optimised for data collection at very low X-ray energies, we show that the anomalous signal can be used to identify multiple orientations in small fragments containing sulphur and/or chloro substituents or to verify recently reported conformations. Although in this specific case we identified the positions of sulphur and chlorine in fragments bound to their protein target, we are confident that this work can be further expanded to additional atoms or ions which often occur in fragments. Finally, our improvements in the understanding of binding orientations will also serve to improve the rational optimisation of SARS-CoV-2 nsp1 fragment hits Full article
(This article belongs to the Special Issue Emerging Topics in Protein Crystallography)
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13 pages, 2432 KiB  
Article
Conformational Disorder Analysis of the Conditionally Disordered Protein CP12 from Arabidopsis thaliana in Its Different Redox States
by Alessandra Del Giudice, Libero Gurrieri, Luciano Galantini, Silvia Fanti, Paolo Trost, Francesca Sparla and Simona Fermani
Int. J. Mol. Sci. 2023, 24(11), 9308; https://doi.org/10.3390/ijms24119308 - 26 May 2023
Cited by 1 | Viewed by 984
Abstract
CP12 is a redox-dependent conditionally disordered protein universally distributed in oxygenic photosynthetic organisms. It is primarily known as a light-dependent redox switch regulating the reductive step of the metabolic phase of photosynthesis. In the present study, a small angle X-ray scattering (SAXS) analysis [...] Read more.
CP12 is a redox-dependent conditionally disordered protein universally distributed in oxygenic photosynthetic organisms. It is primarily known as a light-dependent redox switch regulating the reductive step of the metabolic phase of photosynthesis. In the present study, a small angle X-ray scattering (SAXS) analysis of recombinant Arabidopsis CP12 (AtCP12) in a reduced and oxidized form confirmed the highly disordered nature of this regulatory protein. However, it clearly pointed out a decrease in the average size and a lower level of conformational disorder upon oxidation. We compared the experimental data with the theoretical profiles of pools of conformers generated with different assumptions and show that the reduced form is fully disordered, whereas the oxidized form is better described by conformers comprising both the circular motif around the C-terminal disulfide bond detected in previous structural analysis and the N-terminal disulfide bond. Despite the fact that disulfide bridges are usually thought to confer rigidity to protein structures, in the oxidized AtCP12, their presence coexists with a disordered nature. Our results rule out the existence of significant amounts of structured and compact conformations of free AtCP12 in a solution, even in its oxidized form, thereby highlighting the importance of recruiting partner proteins to complete its structured final folding. Full article
(This article belongs to the Special Issue Emerging Topics in Protein Crystallography)
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25 pages, 2519 KiB  
Article
The Automatic Solution of Macromolecular Crystal Structures via Molecular Replacement Techniques: REMO22 and Its Pipeline
by Benedetta Carrozzini, Giovanni Luca Cascarano and Carmelo Giacovazzo
Int. J. Mol. Sci. 2023, 24(7), 6070; https://doi.org/10.3390/ijms24076070 - 23 Mar 2023
Cited by 1 | Viewed by 1280
Abstract
A description of REMO22, a new molecular replacement program for proteins and nucleic acids, is provided. This program, as with REMO09, can use various types of prior information through appropriate conditional distribution functions. Its efficacy in model searching has been validated through several [...] Read more.
A description of REMO22, a new molecular replacement program for proteins and nucleic acids, is provided. This program, as with REMO09, can use various types of prior information through appropriate conditional distribution functions. Its efficacy in model searching has been validated through several test cases involving proteins and nucleic acids. Although REMO22 can be configured with different protocols according to user directives, it has been developed primarily as an automated tool for determining the crystal structures of macromolecules. To evaluate REMO22’s utility in the current crystallographic environment, its experimental results must be compared favorably with those of the most widely used Molecular Replacement (MR) programs. To accomplish this, we chose two leading tools in the field, PHASER and MOLREP. REMO22, along with MOLREP and PHASER, were included in pipelines that contain two additional steps: phase refinement (SYNERGY) and automated model building (CAB). To evaluate the effectiveness of REMO22, SYNERGY and CAB, we conducted experimental tests on numerous macromolecular structures. The results indicate that REMO22, along with its pipeline REMO22 + SYNERGY + CAB, presents a viable alternative to currently used phasing tools. Full article
(This article belongs to the Special Issue Emerging Topics in Protein Crystallography)
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