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Special Issue "Protein Crystallography in Molecular Biology 2015"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (31 March 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Charles A. Collyer

School of Molecular Bioscience, G08 - Biochemistry Building, The University of Sydney, NSW 2006, Australia
Website | E-Mail
Interests: protein structure and function; anaerobic bacteria; bacterial adhesins

Special Issue Information

Dear Colleagues,

Our understanding of how biological molecules interact is often presented as a number of snapshots of static images derived from bio-molecular crystallography (today, images are increasingly also derived from NMR spectroscopy). We “see” our molecular biology in these images as processes of recognition, biochemical transformation, physical movement, and communication. Being a sub-nano imaging technique, crystallography provides unbiased insight into the complex features of proteins, DNA, and RNA, and their relationships to substrates, inhibitors, and binding partners. The crystal structures of proteins often surprise us because they produce images of molecules as they really are! Many novel gene products are not structured in the ways that we initially perceive them to be; experimentally determined structures enable us to accurately translate genetic information into three dimensions. By identifying particular structural features of biological molecules and then associating them with specific functions, biologists can focus on mechanistic relationships. Understanding such relationships may enable the construction of working models that can usefully drive studies of complex systems in biology. This type of approach, which uses the identification of key elements of structure to start a tertiary discovery process, has been applied successfully in all the life sciences, from biochemistry to cell biology and beyond (into our understanding of evolution).

This Special Issue on protein crystallography for the International Journal of Molecular Sciences will focus on examples in molecular biology where structural data derived from protein crystallography has provided the means of generating unique insights into molecular processes in biology.

Prof. Dr. Charles A. Collyer
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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 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 1600 CHF (Swiss Francs).

Keywords

  • nucleotide sequence recognition
  • structural motifs and function
  • protein families
  • directed evolution and structure
  • structural models and application
  • conformational signaling
  • enzyme mechanism and drug design

Related Special Issue

Published Papers (11 papers)

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Research

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Open AccessArticle Crystal Structure of a Hidden Protein, YcaC, a Putative Cysteine Hydrolase from Pseudomonas aeruginosa, with and without an Acrylamide Adduct
Int. J. Mol. Sci. 2015, 16(7), 15971-15984; doi:10.3390/ijms160715971
Received: 26 April 2015 / Revised: 4 June 2015 / Accepted: 15 June 2015 / Published: 14 July 2015
Cited by 2 | PDF Full-text (4562 KB) | HTML Full-text | XML Full-text
Abstract
As part of the ongoing effort to functionally and structurally characterize virulence factors in the opportunistic pathogen Pseudomonas aeruginosa, we determined the crystal structure of YcaC co-purified with the target protein at resolutions of 2.34 and 2.56 Å without a priori knowledge
[...] Read more.
As part of the ongoing effort to functionally and structurally characterize virulence factors in the opportunistic pathogen Pseudomonas aeruginosa, we determined the crystal structure of YcaC co-purified with the target protein at resolutions of 2.34 and 2.56 Å without a priori knowledge of the protein identity or experimental phases. The three-dimensional structure of YcaC adopts a well-known cysteine hydrolase fold with the putative active site residues conserved. The active site cysteine is covalently bound to propionamide in one crystal form, whereas the second form contains an S-mercaptocysteine. The precise biological function of YcaC is unknown; however, related prokaryotic proteins have functions in antibacterial resistance, siderophore production and NADH biosynthesis. Here, we show that YcaC is exceptionally well conserved across both bacterial and fungal species despite being non-ubiquitous. This suggests that whilst YcaC may not be part of an integral pathway, the function could confer a significant evolutionary advantage to microbial life. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessArticle Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria
Int. J. Mol. Sci. 2015, 16(7), 15287-15308; doi:10.3390/ijms160715287
Received: 30 March 2015 / Revised: 19 June 2015 / Accepted: 24 June 2015 / Published: 7 July 2015
Cited by 4 | PDF Full-text (10515 KB) | HTML Full-text | XML Full-text
Abstract
Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major
[...] Read more.
Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessArticle The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms
Int. J. Mol. Sci. 2015, 16(6), 13004-13022; doi:10.3390/ijms160613004
Received: 27 February 2015 / Revised: 24 April 2015 / Accepted: 13 May 2015 / Published: 9 June 2015
Cited by 1 | PDF Full-text (4322 KB) | HTML Full-text | XML Full-text
Abstract
N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and l-glutamate. In microorganisms and plants, the enzyme functions in the arginine biosynthetic pathway, while in mammals, its major role is to produce the essential co-factor of carbamoyl phosphate synthetase
[...] Read more.
N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and l-glutamate. In microorganisms and plants, the enzyme functions in the arginine biosynthetic pathway, while in mammals, its major role is to produce the essential co-factor of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle. Recent work has shown that several different genes encode enzymes that can catalyze NAG formation. A bifunctional enzyme was identified in certain bacteria, which catalyzes both NAGS and N-acetylglutamate kinase (NAGK) activities, the first two steps of the arginine biosynthetic pathway. Interestingly, these bifunctional enzymes have higher sequence similarity to vertebrate NAGS than those of the classical (mono-functional) bacterial NAGS. Solving the structures for both classical bacterial NAGS and bifunctional vertebrate-like NAGS/K has advanced our insight into the regulation and catalytic mechanisms of NAGS, and the evolutionary relationship between the two NAGS groups. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessArticle Structural Analysis of the Complex between Penta-EF-Hand ALG-2 Protein and Sec31A Peptide Reveals a Novel Target Recognition Mechanism of ALG-2
Int. J. Mol. Sci. 2015, 16(2), 3677-3699; doi:10.3390/ijms16023677
Received: 9 January 2015 / Accepted: 30 January 2015 / Published: 6 February 2015
Cited by 6 | PDF Full-text (4641 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
ALG-2, a 22-kDa penta-EF-hand protein, is involved in cell death, signal transduction, membrane trafficking, etc., by interacting with various proteins in mammalian cells in a Ca2+-dependent manner. Most known ALG-2-interacting proteins contain proline-rich regions in which either PPYPXnYP
[...] Read more.
ALG-2, a 22-kDa penta-EF-hand protein, is involved in cell death, signal transduction, membrane trafficking, etc., by interacting with various proteins in mammalian cells in a Ca2+-dependent manner. Most known ALG-2-interacting proteins contain proline-rich regions in which either PPYPXnYP (type 1 motif) or PXPGF (type 2 motif) is commonly found. Previous X-ray crystal structural analysis of the complex between ALG-2 and an ALIX peptide revealed that the peptide binds to the two hydrophobic pockets. In the present study, we resolved the crystal structure of the complex between ALG-2 and a peptide of Sec31A (outer shell component of coat complex II, COPII; containing the type 2 motif) and found that the peptide binds to the third hydrophobic pocket (Pocket 3). While amino acid substitution of Phe85, a Pocket 3 residue, with Ala abrogated the interaction with Sec31A, it did not affect the interaction with ALIX. On the other hand, amino acid substitution of Tyr180, a Pocket 1 residue, with Ala caused loss of binding to ALIX, but maintained binding to Sec31A. We conclude that ALG-2 recognizes two types of motifs at different hydrophobic surfaces. Furthermore, based on the results of serial mutational analysis of the ALG-2-binding sites in Sec31A, the type 2 motif was newly defined. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Review

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Open AccessReview Thermostable Carbonic Anhydrases in Biotechnological Applications
Int. J. Mol. Sci. 2015, 16(7), 15456-15480; doi:10.3390/ijms160715456
Received: 26 May 2015 / Revised: 1 July 2015 / Accepted: 2 July 2015 / Published: 8 July 2015
Cited by 2 | PDF Full-text (2980 KB) | HTML Full-text | XML Full-text
Abstract
Carbonic anhydrases are ubiquitous metallo-enzymes which catalyze the reversible hydration of carbon dioxide in bicarbonate ions and protons. Recent years have seen an increasing interest in the utilization of these enzymes in CO2 capture and storage processes. However, since this use is
[...] Read more.
Carbonic anhydrases are ubiquitous metallo-enzymes which catalyze the reversible hydration of carbon dioxide in bicarbonate ions and protons. Recent years have seen an increasing interest in the utilization of these enzymes in CO2 capture and storage processes. However, since this use is greatly limited by the harsh conditions required in these processes, the employment of thermostable enzymes, both those isolated by thermophilic organisms and those obtained by protein engineering techniques, represents an interesting possibility. In this review we will provide an extensive description of the thermostable carbonic anhydrases so far reported and the main processes in which these enzymes have found an application. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessReview Protein Crystallography in Vaccine Research and Development
Int. J. Mol. Sci. 2015, 16(6), 13106-13140; doi:10.3390/ijms160613106
Received: 31 March 2015 / Accepted: 1 June 2015 / Published: 9 June 2015
Cited by 6 | PDF Full-text (4148 KB) | HTML Full-text | XML Full-text
Abstract
The use of protein X-ray crystallography for structure-based design of small-molecule drugs is well-documented and includes several notable success stories. However, it is less well-known that structural biology has emerged as a major tool for the design of novel vaccine antigens. Here, we
[...] Read more.
The use of protein X-ray crystallography for structure-based design of small-molecule drugs is well-documented and includes several notable success stories. However, it is less well-known that structural biology has emerged as a major tool for the design of novel vaccine antigens. Here, we review the important contributions that protein crystallography has made so far to vaccine research and development. We discuss several examples of the crystallographic characterization of vaccine antigen structures, alone or in complexes with ligands or receptors. We cover the critical role of high-resolution epitope mapping by reviewing structures of complexes between antigens and their cognate neutralizing, or protective, antibody fragments. Most importantly, we provide recent examples where structural insights obtained via protein crystallography have been used to design novel optimized vaccine antigens. This review aims to illustrate the value of protein crystallography in the emerging discipline of structural vaccinology and its impact on the rational design of vaccines. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessReview A Structural Overview of RNA-Dependent RNA Polymerases from the Flaviviridae Family
Int. J. Mol. Sci. 2015, 16(6), 12943-12957; doi:10.3390/ijms160612943
Received: 1 April 2015 / Revised: 27 May 2015 / Accepted: 28 May 2015 / Published: 8 June 2015
Cited by 3 | PDF Full-text (3057 KB) | HTML Full-text | XML Full-text
Abstract
RNA-dependent RNA polymerases (RdRPs) from the Flaviviridae family are representatives of viral polymerases that carry out RNA synthesis through a de novo initiation mechanism. They share a ≈ 600-residue polymerase core that displays a canonical viral RdRP architecture resembling an encircled right hand
[...] Read more.
RNA-dependent RNA polymerases (RdRPs) from the Flaviviridae family are representatives of viral polymerases that carry out RNA synthesis through a de novo initiation mechanism. They share a ≈ 600-residue polymerase core that displays a canonical viral RdRP architecture resembling an encircled right hand with palm, fingers, and thumb domains surrounding the active site. Polymerase catalytic motifs A–E in the palm and motifs F/G in the fingers are shared by all viral RdRPs with sequence and/or structural conservations regardless of the mechanism of initiation. Different from RdRPs carrying out primer-dependent initiation, Flaviviridae and other de novo RdRPs utilize a priming element often integrated in the thumb domain to facilitate primer-independent initiation. Upon the transition to the elongation phase, this priming element needs to undergo currently unresolved conformational rearrangements to accommodate the growth of the template-product RNA duplex. In the genera of Flavivirus and Pestivirus, the polymerase module in the C-terminal part of the RdRP protein may be regulated in cis by the N-terminal region of the same polypeptide. Either being a methyltransferase in Flavivirus or a functionally unclarified module in Pestivirus, this region could play auxiliary roles for the canonical folding and/or the catalysis of the polymerase, through defined intra-molecular interactions. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
Open AccessReview Structural Basis for Carbapenem-Hydrolyzing Mechanisms of Carbapenemases Conferring Antibiotic Resistance
Int. J. Mol. Sci. 2015, 16(5), 9654-9692; doi:10.3390/ijms16059654
Received: 3 February 2015 / Revised: 21 April 2015 / Accepted: 22 April 2015 / Published: 29 April 2015
Cited by 4 | PDF Full-text (7243 KB) | HTML Full-text | XML Full-text
Abstract
Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are β-lactam antimicrobial agents. Because carbapenems have the broadest spectra among all β-lactams and are primarily used to treat infections by multi-resistant Gram-negative bacteria, the emergence and spread of carbapenemases became a major public health concern.
[...] Read more.
Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are β-lactam antimicrobial agents. Because carbapenems have the broadest spectra among all β-lactams and are primarily used to treat infections by multi-resistant Gram-negative bacteria, the emergence and spread of carbapenemases became a major public health concern. Carbapenemases are the most versatile family of β-lactamases that are able to hydrolyze carbapenems and many other β-lactams. According to the dependency of divalent cations for enzyme activation, carbapenemases can be divided into metallo-carbapenemases (zinc-dependent class B) and non-metallo-carbapenemases (zinc-independent classes A, C, and D). Many studies have provided various carbapenemase structures. Here we present a comprehensive and systematic review of three-dimensional structures of carbapenemase-carbapenem complexes as well as those of carbapenemases. We update recent studies in understanding the enzymatic mechanism of each class of carbapenemase, and summarize structural insights about regions and residues that are important in acquiring the carbapenemase activity. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessReview Unzippers, Resolvers and Sensors: A Structural and Functional Biochemistry Tale of RNA Helicases
Int. J. Mol. Sci. 2015, 16(2), 2269-2293; doi:10.3390/ijms16022269
Received: 24 November 2014 / Revised: 9 January 2015 / Accepted: 12 January 2015 / Published: 22 January 2015
Cited by 5 | PDF Full-text (12403 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The centrality of RNA within the biological world is an irrefutable fact that currently attracts increasing attention from the scientific community. The panoply of functional RNAs requires the existence of specific biological caretakers, RNA helicases, devoted to maintain the proper folding of those
[...] Read more.
The centrality of RNA within the biological world is an irrefutable fact that currently attracts increasing attention from the scientific community. The panoply of functional RNAs requires the existence of specific biological caretakers, RNA helicases, devoted to maintain the proper folding of those molecules, resolving unstable structures. However, evolution has taken advantage of the specific position and characteristics of RNA helicases to develop new functions for these proteins, which are at the interface of the basic processes for transference of information from DNA to proteins. RNA helicases are involved in many biologically relevant processes, not only as RNA chaperones, but also as signal transducers, scaffolds of molecular complexes, and regulatory elements. Structural biology studies during the last decade, founded in X-ray crystallography, have characterized in detail several RNA-helicases. This comprehensive review summarizes the structural knowledge accumulated in the last two decades within this family of proteins, with special emphasis on the structure-function relationships of the most widely-studied families of RNA helicases: the DEAD-box, RIG-I-like and viral NS3 classes. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessReview Structure and Function of SET and MYND Domain-Containing Proteins
Int. J. Mol. Sci. 2015, 16(1), 1406-1428; doi:10.3390/ijms16011406
Received: 5 December 2014 / Accepted: 5 January 2015 / Published: 8 January 2015
Cited by 11 | PDF Full-text (12506 KB) | HTML Full-text | XML Full-text
Abstract
SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell
[...] Read more.
SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control. During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle. SMYD proteins are also of therapeutic interest due to the growing list of carcinomas and cardiovascular diseases linked to SMYD overexpression or dysfunction making them a putative target for drug intervention. This review will examine the biological relevance and gather all of the current structural data of SMYD proteins. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
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Open AccessReview Molecular Mechanisms of Host Cytoskeletal Rearrangements by Shigella Invasins
Int. J. Mol. Sci. 2014, 15(10), 18253-18266; doi:10.3390/ijms151018253
Received: 31 July 2014 / Revised: 23 September 2014 / Accepted: 25 September 2014 / Published: 10 October 2014
Cited by 3 | PDF Full-text (2803 KB) | HTML Full-text | XML Full-text
Abstract
Pathogen-induced reorganization of the host cell cytoskeleton is a common strategy utilized in host cell invasion by many facultative intracellular bacteria, such as Shigella, Listeria, enteroinvasive E. coli and Salmonella. Shigella is an enteroinvasive intracellular pathogen that preferentially infects human
[...] Read more.
Pathogen-induced reorganization of the host cell cytoskeleton is a common strategy utilized in host cell invasion by many facultative intracellular bacteria, such as Shigella, Listeria, enteroinvasive E. coli and Salmonella. Shigella is an enteroinvasive intracellular pathogen that preferentially infects human epithelial cells and causes bacillary dysentery. Invasion of Shigella into intestinal epithelial cells requires extensive remodeling of the actin cytoskeleton with the aid of pathogenic effector proteins injected into the host cell by the activity of the type III secretion system. These so-called Shigella invasins, including IpaA, IpaC, IpgB1, IpgB2 and IpgD, modulate the actin-regulatory system in a concerted manner to guarantee efficient entry of the bacteria into host cells. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)

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