scholarly journals MeLAD: an integrated resource for metalloenzyme-ligand associations

2019 ◽  
Author(s):  
Gen Li ◽  
Yu Su ◽  
Yu-Hang Yan ◽  
Jia-Yi Peng ◽  
Qing-Qing Dai ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Metal Binding ◽  
Metal Ion ◽  
Structural Data ◽  
Structural Similarity ◽  
Functional Class ◽  
Supplementary Information ◽  
Biological Processes ◽  
Ligand Interactions ◽  
Data Source

Abstract Motivation Metalloenzymes are attractive targets for therapeutic intervention owing to their central roles in various biological processes and pathological situations. The fast-growing body of structural data on metalloenzyme-ligand interactions is facilitating efficient drug discovery targeting metalloenzymes. However, there remains a shortage of specific databases that can provide centralized, interconnected information exclusive to metalloenzyme-ligand associations. Results We created a Metalloenzyme-Ligand Association Database (MeLAD), which is designed to provide curated structural data and information exclusive to metalloenzyme-ligand interactions, and more uniquely, present expanded associations that are represented by metal-binding pharmacophores (MBPs), metalloenzyme structural similarity (MeSIM) and ligand chemical similarity (LigSIM). MeLAD currently contains 6086 structurally resolved interactions of 1416 metalloenzymes with 3564 ligands, of which classical metal-binding, non-classical metal-binding, non-metal-binding and metal water-bridging interactions account for 63.0%, 2.3%, 34.4% and 0.3%, respectively. A total of 263 monodentate, 191 bidentate and 15 tridentate MBP chemotypes were included in MeLAD, which are linked to different active site metal ions and coordination modes. 3726 and 52 740 deductive metalloenzyme-ligand associations by MeSIM and LigSIM analyses, respectively, were included in MeLAD. An online server is provided for users to conduct metalloenzyme profiling prediction for small molecules of interest. MeLAD is searchable by multiple criteria, e.g. metalloenzyme name, ligand identifier, functional class, bioinorganic class, metal ion and metal-containing cofactor, which will serve as a valuable, integrative data source to foster metalloenzyme related research, particularly involved in drug discovery targeting metalloenzymes. Availability and implementation MeLAD is accessible at https://melad.ddtmlab.org. Supplementary information Supplementary data are available at Bioinformatics online.

Na+/K+exchange switches the catalytic apparatus of potassium-dependent plantL-asparaginase

2014 ◽  
Vol 70 (7) ◽  
pp. 1854-1872 ◽  
Author(s):  
Magdalena Bejger ◽  
Barbara Imiolczyk ◽  
Damien Clavel ◽  
Miroslaw Gilski ◽  
Agnieszka Pajak ◽  
...  
Keyword(s):  
Alkali Metal ◽  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Catalytic Mechanism ◽  
Structural Data ◽  
Activation Loop ◽  
Plant Type ◽  
Substrate Preferences ◽  
Autocatalytic Cleavage

Plant-type L-asparaginases, which are a subclass of the Ntn-hydrolase family, are divided into potassium-dependent and potassium-independent enzymes with different substrate preferences. While the potassium-independent enzymes have already been well characterized, there are no structural data for any of the members of the potassium-dependent group to illuminate the intriguing dependence of their catalytic mechanism on alkali-metal cations. Here, three crystal structures of a potassium-dependent plant-type L-asparaginase fromPhaseolus vulgaris(PvAspG1) differing in the type of associated alkali metal ions (K+, Na+or both) are presented and the structural consequences of the different ions are correlated with the enzyme activity. As in all plant-type L-asparaginases, immature PvAspG1 is a homodimer of two protein chains, which both undergo autocatalytic cleavage to α and β subunits, thus creating the mature heterotetramer or dimer of heterodimers (αβ)2. The αβ subunits of PvAspG1 are folded similarly to the potassium-independent enzymes, with a sandwich of two β-sheets flanked on each side by a layer of helices. In addition to the `sodium loop' (here referred to as the `stabilization loop') known from potassium-independent plant-type asparaginases, the potassium-dependent PvAspG1 enzyme contains another alkali metal-binding loop (the `activation loop') in subunit α (residues Val111–Ser118). The active site of PvAspG1 is located between these two metal-binding loops and in the immediate neighbourhood of three residues, His117, Arg224 and Glu250, acting as a catalytic switch, which is a novel feature that is identified in plant-type L-asparaginases for the first time. A comparison of the three PvAspG1 structures demonstrates how the metal ion bound in the activation loop influences its conformation, setting the catalytic switch to ON (when K+is coordinated) or OFF (when Na+is coordinated) to respectively allow or prevent anchoring of the reaction substrate/product in the active site. Moreover, it is proposed that Ser118, the last residue of the activation loop, is involved in the potassium-dependence mechanism. The PvAspG1 structures are discussed in comparison with those of potassium-independent L-asparaginases (LlA, EcAIII and hASNase3) and those of other Ntn-hydrolases (AGA and Tas1), as well as in the light of noncrystallographic studies.

scholarly journals COVID-19 Docking Server: a meta server for docking small molecules, peptides and antibodies against potential targets of COVID-19

2020 ◽  
Vol 36 (20) ◽  
pp. 5109-5111 ◽  
Author(s):  
Ren Kong ◽  
Guangbo Yang ◽  
Rui Xue ◽  
Ming Liu ◽  
Feng Wang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Drug Discovery ◽  
Small Molecules ◽  
Web Server ◽  
Supplementary Information ◽  
Binding Modes ◽  
Supplementary Data ◽  
Virus Life Cycle ◽  
Ligand Interactions ◽  
New Type

Abstract Motivation The coronavirus disease 2019 (COVID-19) caused by a new type of coronavirus has been emerging from China and led to thousands of death globally since December 2019. Despite many groups have engaged in studying the newly emerged virus and searching for the treatment of COVID-19, the understanding of the COVID-19 target–ligand interactions represents a key challenge. Herein, we introduce COVID-19 Docking Server, a web server that predicts the binding modes between COVID-19 targets and the ligands including small molecules, peptides and antibodies. Results Structures of proteins involved in the virus life cycle were collected or constructed based on the homologs of coronavirus, and prepared ready for docking. The meta-platform provides a free and interactive tool for the prediction of COVID-19 target–ligand interactions and following drug discovery for COVID-19. Availability and implementation http://ncov.schanglab.org.cn. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Insight into the Function of Active Site Residues in the Catalytic Mechanism of Human Ferrochelatase

2021 ◽  
Author(s):  
Amy E. Medlock ◽  
Wided Najahi-Missaoui ◽  
Mesafint T. Shiferaw ◽  
Angela N. Albetel ◽  
William N. Lanzilotta ◽  
...  
Keyword(s):  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Catalytic Mechanism ◽  
Structural Data ◽  
Active Site Residues ◽  
Proton Abstraction ◽  
Product Release ◽  
Iron Delivery ◽  
High Level

Ferrochelatase catalyzes the insertion of ferrous iron into a porphyrin macrocycle to produce the essential cofactor, heme. In humans this enzyme not only catalyzes the terminal step, but also serves a regulatory step in the heme synthesis pathway. Over a dozen crystal structures of human ferrochelatase have been solved and many variants have been characterized kinetically. In addition, hydrogen deuterium exchange, resonance Raman, molecular dynamics, and high level quantum mechanic studies have added to our understanding of  the catalytic cycle of the enzyme. However, an understanding of how the metal ion is delivered and the specific role that active site residues play in catalysis remain open questions. Data are consistent with metal binding and insertion occurring from the side opposite from where pyrrole proton abstraction takes place. To better understand iron delivery and binding as well as the role of conserved residues in the active site, we have constructed and characterized a series of enzyme variants. Crystallographic studies as well as rescue and kinetic analysis of variants were performed. Data from these studies are consistent with the M76 residue playing a role in active site metal binding and formation of a weak iron protein ligand being necessary for product release. Additionally, structural data support a role for E343 in proton abstraction and product release in coordination with a peptide loop composed of Q302, S303 and K304 that act a metal sensor.

scholarly journals Mass Spectrometry-Based Structural Proteomics for Metal Ion/Protein Binding Studies

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 135
Author(s):  
Yanchun Lin ◽  
Michael L. Gross
Keyword(s):  
Mass Spectrometry ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Metal Binding ◽  
Metal Ion ◽  
Photochemical Oxidation ◽  
Structural Proteomics ◽  
Binding Studies ◽  
Ligand Interactions ◽  
Amino Acid Labeling

Metal ions are critical for the biological and physiological functions of many proteins. Mass spectrometry (MS)-based structural proteomics is an ever-growing field that has been adopted to study protein and metal ion interactions. Native MS offers information on metal binding and its stoichiometry. Footprinting approaches coupled with MS, including hydrogen/deuterium exchange (HDX), “fast photochemical oxidation of proteins” (FPOP) and targeted amino-acid labeling, identify binding sites and regions undergoing conformational changes. MS-based titration methods, including “protein–ligand interactions by mass spectrometry, titration and HD exchange” (PLIMSTEX) and “ligand titration, fast photochemical oxidation of proteins and mass spectrometry” (LITPOMS), afford binding stoichiometry, binding affinity, and binding order. These MS-based structural proteomics approaches, their applications to answer questions regarding metal ion protein interactions, their limitations, and recent and potential improvements are discussed here. This review serves as a demonstration of the capabilities of these tools and as an introduction to wider applications to solve other questions.

scholarly journals CheckMyMetal: a macromolecular metal-binding validation tool

2017 ◽  
Vol 73 (3) ◽  
pp. 223-233 ◽  
Author(s):  
Heping Zheng ◽  
David R. Cooper ◽  
Przemyslaw J. Porebski ◽  
Ivan G. Shabalin ◽  
Katarzyna B. Handing ◽  
...  
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Metal Ion ◽  
Data Bank ◽  
Biological Processes ◽  
Metal Binding Site ◽  
Metal Binding Sites ◽  
Metal Site ◽  
Validation Tool ◽  
Specific Metal

Metals are essential in many biological processes, and metal ions are modeled in roughly 40% of the macromolecular structures in the Protein Data Bank (PDB). However, a significant fraction of these structures contain poorly modeled metal-binding sites.CheckMyMetal(CMM) is an easy-to-use metal-binding site validation server for macromolecules that is freely available at http://csgid.org/csgid/metal_sites. TheCMMserver can detect incorrect metal assignments as well as geometrical and other irregularities in the metal-binding sites. Guidelines for metal-site modeling and validation in macromolecules are illustrated by several practical examples grouped by the type of metal. These examples showCMMusers (and crystallographers in general) problems they may encounter during the modeling of a specific metal ion.

Structures of c-di-GMP/cGAMP degrading phosphodiesterase VcEAL: identification of a novel conformational switch and its implication

2019 ◽  
Vol 476 (21) ◽  
pp. 3333-3353 ◽  
Author(s):  
Malti Yadav ◽  
Kamalendu Pal ◽  
Udayaditya Sen
Keyword(s):  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Triosephosphate Isomerase ◽  
Catalytic Mechanism ◽  
Degradation Mechanism ◽  
Structural Basis ◽  
Conserved Residues ◽  
Phosphodiester Bond ◽  
Cyclic Dinucleotides

Cyclic dinucleotides (CDNs) have emerged as the central molecules that aid bacteria to adapt and thrive in changing environmental conditions. Therefore, tight regulation of intracellular CDN concentration by counteracting the action of dinucleotide cyclases and phosphodiesterases (PDEs) is critical. Here, we demonstrate that a putative stand-alone EAL domain PDE from Vibrio cholerae (VcEAL) is capable to degrade both the second messenger c-di-GMP and hybrid 3′3′-cyclic GMP–AMP (cGAMP). To unveil their degradation mechanism, we have determined high-resolution crystal structures of VcEAL with Ca2+, c-di-GMP-Ca2+, 5′-pGpG-Ca2+ and cGAMP-Ca2+, the latter provides the first structural basis of cGAMP hydrolysis. Structural studies reveal a typical triosephosphate isomerase barrel-fold with substrate c-di-GMP/cGAMP bound in an extended conformation. Highly conserved residues specifically bind the guanine base of c-di-GMP/cGAMP in the G2 site while the semi-conserved nature of residues at the G1 site could act as a specificity determinant. Two metal ions, co-ordinated with six stubbornly conserved residues and two non-bridging scissile phosphate oxygens of c-di-GMP/cGAMP, activate a water molecule for an in-line attack on the phosphodiester bond, supporting two-metal ion-based catalytic mechanism. PDE activity and biofilm assays of several prudently designed mutants collectively demonstrate that VcEAL active site is charge and size optimized. Intriguingly, in VcEAL-5′-pGpG-Ca2+ structure, β5–α5 loop adopts a novel conformation that along with conserved E131 creates a new metal-binding site. This novel conformation along with several subtle changes in the active site designate VcEAL-5′-pGpG-Ca2+ structure quite different from other 5′-pGpG bound structures reported earlier.

19F-NMR in Target-based Drug Discovery

2019 ◽  
Vol 26 (26) ◽  
pp. 4964-4983 ◽  
Author(s):  
CongBao Kang
Keyword(s):  
Drug Discovery ◽  
Conformational Changes ◽  
Protein Structures ◽  
19F Nmr ◽  
Binding Affinities ◽  
Protein Ligand Interactions ◽  
Compound Libraries ◽  
Ligand Interactions ◽  
Reference Ligand ◽  
Hit Identification

Solution NMR spectroscopy plays important roles in understanding protein structures, dynamics and protein-protein/ligand interactions. In a target-based drug discovery project, NMR can serve an important function in hit identification and lead optimization. Fluorine is a valuable probe for evaluating protein conformational changes and protein-ligand interactions. Accumulated studies demonstrate that 19F-NMR can play important roles in fragment- based drug discovery (FBDD) and probing protein-ligand interactions. This review summarizes the application of 19F-NMR in understanding protein-ligand interactions and drug discovery. Several examples are included to show the roles of 19F-NMR in confirming identified hits/leads in the drug discovery process. In addition to identifying hits from fluorinecontaining compound libraries, 19F-NMR will play an important role in drug discovery by providing a fast and robust way in novel hit identification. This technique can be used for ranking compounds with different binding affinities and is particularly useful for screening competitive compounds when a reference ligand is available.

scholarly journals Genome-wide analysis and expression profile of the bZIP gene family in poplar

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kai Zhao ◽  
Song Chen ◽  
Wenjing Yao ◽  
Zihan Cheng ◽  
Boru Zhou ◽  
...  
Keyword(s):  
Salt Stress ◽  
Systems Biology ◽  
Gene Family ◽  
Stress Responses ◽  
Metal Ion ◽  
Gene Networks ◽  
Expression Patterns ◽  
Gene Set Enrichment Analysis ◽  
Specific Gene ◽  
Biological Processes

Abstract Background The bZIP gene family, which is widely present in plants, participates in varied biological processes including growth and development and stress responses. How do the genes regulate such biological processes? Systems biology is powerful for mechanistic understanding of gene functions. However, such studies have not yet been reported in poplar. Results In this study, we identified 86 poplar bZIP transcription factors and described their conserved domains. According to the results of phylogenetic tree, we divided these members into 12 groups with specific gene structures and motif compositions. The corresponding genes that harbor a large number of segmental duplication events are unevenly distributed on the 17 poplar chromosomes. In addition, we further examined collinearity between these genes and the related genes from six other species. Evidence from transcriptomic data indicated that the bZIP genes in poplar displayed different expression patterns in roots, stems, and leaves. Furthermore, we identified 45 bZIP genes that respond to salt stress in the three tissues. We performed co-expression analysis on the representative genes, followed by gene set enrichment analysis. The results demonstrated that tissue differentially expressed genes, especially the co-expressing genes, are mainly involved in secondary metabolic and secondary metabolite biosynthetic processes. However, salt stress responsive genes and their co-expressing genes mainly participate in the regulation of metal ion transport, and methionine biosynthetic. Conclusions Using comparative genomics and systems biology approaches, we, for the first time, systematically explore the structures and functions of the bZIP gene family in poplar. It appears that the bZIP gene family plays significant roles in regulation of poplar development and growth and salt stress responses through differential gene networks or biological processes. These findings provide the foundation for genetic breeding by engineering target regulators and corresponding gene networks into poplar lines.

scholarly journals Acylated Anthocyanins from Red Cabbage and Purple Sweet Potato Can Bind Metal Ions and Produce Stable Blue Colors

2021 ◽  
Vol 22 (9) ◽  
pp. 4551
Author(s):  
Julie-Anne Fenger ◽  
Gregory T. Sigurdson ◽  
Rebecca J. Robbins ◽  
Thomas M. Collins ◽  
M. Mónica Giusti ◽  
...  
Keyword(s):  
Metal Ions ◽  
Sweet Potato ◽  
Metal Binding ◽  
Metal Ion ◽  
High Resolution Mass Spectrometry ◽  
Large Set ◽  
Water Addition ◽  
Red Cabbage ◽  
Aluminum Ions ◽  
Purple Sweet Potato

Red cabbage (RC) and purple sweet potato (PSP) are naturally rich in acylated cyanidin glycosides that can bind metal ions and develop intramolecular π-stacking interactions between the cyanidin chromophore and the phenolic acyl residues. In this work, a large set of RC and PSP anthocyanins was investigated for its coloring properties in the presence of iron and aluminum ions. Although relatively modest, the structural differences between RC and PSP anthocyanins, i.e., the acylation site at the external glucose of the sophorosyl moiety (C2-OH for RC vs. C6-OH for PSP) and the presence of coordinating acyl groups (caffeoyl) in PSP anthocyanins only, made a large difference in the color expressed by their metal complexes. For instance, the Al3+-induced bathochromic shifts for RC anthocyanins reached ca. 50 nm at pH 6 and pH 7, vs. at best ca. 20 nm for PSP anthocyanins. With Fe2+ (quickly oxidized to Fe3+ in the complexes), the bathochromic shifts for RC anthocyanins were higher, i.e., up to ca. 90 nm at pH 7 and 110 nm at pH 5.7. A kinetic analysis at different metal/ligand molar ratios combined with an investigation by high-resolution mass spectrometry suggested the formation of metal–anthocyanin complexes of 1:1, 1:2, and 1:3 stoichiometries. Contrary to predictions based on steric hindrance, acylation by noncoordinating acyl residues favored metal binding and resulted in complexes having much higher molar absorption coefficients. Moreover, the competition between metal binding and water addition to the free ligands (leading to colorless forms) was less severe, although very dependent on the acylation site(s). Overall, anthocyanins from purple sweet potato, and even more from red cabbage, have a strong potential for development as food colorants expressing red to blue hues depending on pH and metal ion.

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