scholarly journals Structural insight into arginine methylation by the mouse protein arginine methyltransferase 7: a zinc finger freezes the mimic of the dimeric state into a single active site

2014 ◽  
Vol 70 (9) ◽  
pp. 2401-2412 ◽  
Author(s):  
Vincent Cura ◽  
Nathalie Troffer-Charlier ◽  
Jean-Marie Wurtz ◽  
Luc Bonnefond ◽  
Jean Cavarelli
Keyword(s):  
Crystal Structure ◽  
Zinc Finger ◽  
Active Site ◽  
Rna Splicing ◽  
Structural Features ◽  
Arginine Methylation ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Damage Repair ◽  
The Family

Protein arginine methyltransferase 7 (PRMT7) is a type III arginine methyltransferase which has been implicated in several biological processes such as transcriptional regulation, DNA damage repair, RNA splicing, cell differentiation and metastasis. PRMT7 is a unique but less characterized member of the family of PRMTs. The crystal structure of full-length PRMT7 fromMus musculusrefined at 1.7 Å resolution is described. The PRMT7 structure is composed of two catalytic modules in tandem forming a pseudo-dimer and contains only one AdoHcy molecule bound to the N-terminal module. The high-resolution crystal structure presented here revealed several structural features showing that the second active site is frozen in an inactive state by a conserved zinc finger located at the junction between the two PRMT modules and by the collapse of two degenerated AdoMet-binding loops.

scholarly journals Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1

2017 ◽  
Vol 114 (14) ◽  
pp. 3625-3630 ◽  
Author(s):  
Matthijs J. van Haren ◽  
Nils Marechal ◽  
Nathalie Troffer-Charlier ◽  
Agostino Cianciulli ◽  
Gianluca Sbardella ◽  
...  
Keyword(s):  
Transition State ◽  
Active Site ◽  
Arginine Methylation ◽  
Eukaryotic Cells ◽  
Structural Studies ◽  
Potential Therapeutic Target ◽  
Arginine Methyltransferase ◽  
Transient Nature ◽  
The Family ◽  
Covalently Linked

Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics. These constructs were found to be potent CARM1 inhibitors and also formed stable complexes with the enzyme. High-resolution crystal structures of CARM1 in complex with these compounds confirm a mode of binding that is indeed reflective of the transition state at the CARM1 active site. Given the transient nature of PRMT–substrate complexes, such transition state mimics represent valuable chemical tools for structural studies aimed at deciphering the regulation of arginine methylation mediated by the family of arginine methyltransferases.

scholarly journals Non-Histone Arginine Methylation by Protein Arginine Methyltransferases

2020 ◽  
Vol 21 (7) ◽  
pp. 699-712 ◽  
Author(s):  
Ayad A. Al-Hamashi ◽  
Krystal Diaz ◽  
Rong Huang
Keyword(s):  
Rna Splicing ◽  
Arginine Methylation ◽  
Aberrant Expression ◽  
Histone Protein ◽  
Arginine Methyltransferase ◽  
Protein Arginine Methyltransferases ◽  
Protein Substrates ◽  
Damage Repair ◽  
Multiple Abnormalities ◽  
Histone Arginine Methylation

Protein arginine methyltransferase (PRMT) enzymes play a crucial role in RNA splicing, DNA damage repair, cell signaling, and differentiation. Arginine methylation is a prominent posttransitional modification of histones and various non-histone proteins that can either activate or repress gene expression. The aberrant expression of PRMTs has been linked to multiple abnormalities, notably cancer. Herein, we review a number of non-histone protein substrates for all nine members of human PRMTs and how PRMT-mediated non-histone arginine methylation modulates various diseases. Additionally, we highlight the most recent clinical studies for several PRMT inhibitors.

scholarly journals Structure, Activity and Function of the Protein Arginine Methyltransferase 6

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 951
Author(s):  
Somlee Gupta ◽  
Rajashekar Varma Kadumuri ◽  
Anjali Kumari Singh ◽  
Sreenivas Chavali ◽  
Arunkumar Dhayalan
Keyword(s):  
Viral Infections ◽  
Global Gene Expression ◽  
Structural Features ◽  
Arginine Methylation ◽  
Type I ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Wide Range ◽  
Arginine Residues ◽  
And Function

Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. PRMT6 introduces asymmetric dimethylation modification in the histone 3 at arginine 2 (H3R2me2a) and facilitates epigenetic regulation of global gene expression. In addition to histones, PRMT6 methylates a wide range of cellular proteins and regulates their functions. Here, we discuss (i) the biochemical aspects of enzyme kinetics, (ii) the structural features of PRMT6 and (iii) the diverse functional outcomes of PRMT6 mediated arginine methylation. Finally, we highlight how dysregulation of PRMT6 is implicated in various types of cancers and response to viral infections.

Structural insights into dihydroxylation of terephthalate, a product of polyethylene terephthalate degradation

2022 ◽  
Author(s):  
Jai Krishna Mahto ◽  
Neetu Neetu ◽  
Monica Sharma ◽  
Monika Dubey ◽  
Bhanu Prakash Vellanki ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Substrate Specificity ◽  
Polyethylene Terephthalate ◽  
Active Site ◽  
Catalytic Domain ◽  
Structural Features ◽  
Comamonas Testosteroni ◽  
Plastic Pollution ◽  
Microbial Utilization ◽  
Steady State Kinetics

Biodegradation of terephthalate (TPA) is a highly desired catabolic process for the bacterial utilization of this Polyethylene terephthalate (PET) depolymerization product, but to date, the structure of terephthalate dioxygenase (TPDO), a Rieske oxygenase (RO) that catalyzes the dihydroxylation of TPA to a cis -diol is unavailable. In this study, we characterized the steady-state kinetics and first crystal structure of TPDO from Comamonas testosteroni KF1 (TPDO KF1 ). The TPDO KF1 exhibited the substrate specificity for TPA ( k cat / K m = 57 ± 9 mM −1 s −1 ). The TPDO KF1 structure harbors characteristics RO features as well as a unique catalytic domain that rationalizes the enzyme’s function. The docking and mutagenesis studies reveal that its substrate specificity to TPA is mediated by Arg309 and Arg390 residues, two residues positioned on opposite faces of the active site. Additionally, residue Gln300 is also proven to be crucial for the activity, its substitution to alanine decreases the activity ( k cat ) by 80%. Together, this study delineates the structural features that dictate the substrate recognition and specificity of TPDO. Importance The global plastic pollution has become the most pressing environmental issue. Recent studies on enzymes depolymerizing polyethylene terephthalate plastic into terephthalate (TPA) show some potential in tackling this. Microbial utilization of this released product, TPA is an emerging and promising strategy for waste-to-value creation. Research from the last decade has discovered terephthalate dioxygenase (TPDO), as being responsible for initiating the enzymatic degradation of TPA in a few Gram-negative and Gram-positive bacteria. Here, we have determined the crystal structure of TPDO from Comamonas testosteroni KF1 and revealed that it possesses a unique catalytic domain featuring two basic residues in the active site to recognize TPA. Biochemical and mutagenesis studies demonstrated the crucial residues responsible for the substrate specificity of this enzyme.

scholarly journals The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors

2019 ◽  
Vol 20 (15) ◽  
pp. 3840 ◽  
Author(s):  
Sun ◽  
Wang ◽  
Yang ◽  
Zhu ◽  
Wu ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Arginine Methylation ◽  
Free Energy Calculations ◽  
Protein Arginine Methyltransferase ◽  
Dynamic Simulations ◽  
Arginine Methyltransferase ◽  
Diverse Range ◽  
Protein Arginine Methyltransferase 1 ◽  
Canonical Wnt ◽  
Tetrazole Derivatives

Protein arginine methyltransferase 1 (PRMT1) can catalyze protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes. The dysregulation of PRMT1 is involved in a diverse range of diseases, including cancer. Therefore, there is an urgent need to develop novel and potent PRMT1 inhibitors. In the current manuscript, a series of 1-substituted 1H-tetrazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and five compounds demonstrated significant inhibitory effects against PRMT1. The most potent PRMT1 inhibitor, compound 9a, displayed non-competitive pattern with respect to either SAM or substrate arginine, and showed the strong selectivity to PRMT1 compared to PRMT5, which belongs to the type II PRMT family. It was observed that the compound 9a inhibited the functions of PRMT1 and relative factors within this pathway, and down-regulated the canonical Wnt/β-catenin signaling pathway. The binding of compound 9a to PRMT1 was carefully analyzed by using molecular dynamic simulations and binding free energy calculations. These studies demonstrate that 9a was a potent PRMT1 inhibitor, which could be used as lead compound for further drug discovery.

scholarly journals A trapped human PPM1A–phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity

2018 ◽  
Vol 293 (21) ◽  
pp. 7993-8008 ◽  
Author(s):  
Subrata Debnath ◽  
Dalibor Kosek ◽  
Harichandra D. Tagad ◽  
Stewart R. Durell ◽  
Daniel H. Appella ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Metal Ions ◽  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Catalytic Domain ◽  
Protein Phosphatases ◽  
Random Order ◽  
Structural Features

Metal-dependent protein phosphatases (PPM) are evolutionarily unrelated to other serine/threonine protein phosphatases and are characterized by their requirement for supplementation with millimolar concentrations of Mg2+ or Mn2+ ions for activity in vitro. The crystal structure of human PPM1A (also known as PP2Cα), the first PPM structure determined, displays two tightly bound Mn2+ ions in the active site and a small subdomain, termed the Flap, located adjacent to the active site. Some recent crystal structures of bacterial or plant PPM phosphatases have disclosed two tightly bound metal ions and an additional third metal ion in the active site. Here, the crystal structure of the catalytic domain of human PPM1A, PPM1Acat, complexed with a cyclic phosphopeptide, c(MpSIpYVA), a cyclized variant of the activation loop of p38 MAPK (a physiological substrate of PPM1A), revealed three metal ions in the active site. The PPM1Acat D146E–c(MpSIpYVA) complex confirmed the presence of the anticipated third metal ion in the active site of metazoan PPM phosphatases. Biophysical and computational methods suggested that complex formation results in a slightly more compact solution conformation through reduced conformational flexibility of the Flap subdomain. We also observed that the position of the substrate in the active site allows solvent access to the labile third metal-binding site. Enzyme kinetics of PPM1Acat toward a phosphopeptide substrate supported a random-order, bi-substrate mechanism, with substantial interaction between the bound substrate and the labile metal ion. This work illuminates the structural and thermodynamic basis of an innate mechanism regulating the activity of PPM phosphatases.

scholarly journals Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

2016 ◽  
Vol 291 (35) ◽  
pp. 18299-18308 ◽  
Author(s):  
Kanishk Jain ◽  
Rebeccah A. Warmack ◽  
Erik W. Debler ◽  
Andrea Hadjikyriacou ◽  
Peter Stavropoulos ◽  
...  
Keyword(s):  
Active Site ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Product Specificity

Crystal Structure of Guanidinoacetate Methyltransferase from Rat Liver: A Model Structure of Protein Arginine Methyltransferase

2002 ◽  
Vol 320 (2) ◽  
pp. 223-235 ◽  
Author(s):  
Junichi Komoto ◽  
Yafei Huang ◽  
Yoshimi Takata ◽  
Taro Yamada ◽  
Kiyoshi Konishi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Rat Liver ◽  
Model Structure ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase

scholarly journals Crystal Structure of Inorganic Pyrophosphatase From Schistosoma japonicum Reveals the Mechanism of Chemicals and Substrate Inhibition

2021 ◽  
Vol 9 ◽  
Author(s):  
Qun-Feng Wu ◽  
Wei-Si Wang ◽  
Shen-Bo Chen ◽  
Bin Xu ◽  
Yong-Dong Li ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Schistosoma Japonicum ◽  
Active Site ◽  
Substrate Inhibition ◽  
Structural Features ◽  
Inorganic Pyrophosphatase ◽  
Metabolic Pathway Analysis ◽  
Inorganic Pyrophosphate ◽  
X Ray Crystallography ◽  
Pi Complex

Soluble inorganic pyrophosphatases (PPases) are essential for facilitating the growth and development of organisms, making them attractive functional proteins. To provide insight into the molecular basis of PPases in Schistosoma japonicum (SjPPase), we expressed the recombinant SjPPase, analyzed the hydrolysis mechanism of inorganic pyrophosphate (PPi), and measured its activity. Moreover, we solved the crystal structure of SjPPase in complex with orthophosphate (Pi) and performed PPi and methylene diphosphonic acid (MDP) docking into the active site. Our results suggest that the SjPPase possesses PPi hydrolysis activity, and the activity declines with increased MDP or NaF concentration. However, the enzyme shows unexpected substrate inhibition properties. Through PPi metabolic pathway analysis, the physiological action of substrate inhibition might be energy saving, adaptably cytoprotective, and biosynthetic rate regulating. Furthermore, the structure of apo-SjPPase and SjPPase with Pi has been solved at 2.6 and 2.3 Å, respectively. The docking of PPi into the active site of the SjPPase-Pi complex revealed that substrate inhibition might result from blocking Pi exit due to excess PPi in the SjPPase-Pi complex of the catalytic cycle. Our results revealed the structural features of apo-SjPPase and the SjPPase-Pi complex by X-ray crystallography, providing novel insights into the physiological functions of PPase in S. japonicum without the PPi transporter and the mechanism of its substrate inhibition.

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