scholarly journals A promiscuous ancestral enzyme´s structure unveils protein variable regions of the highly diverse metallo-β-lactamase family

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Pablo Perez-Garcia ◽  
Stefanie Kobus ◽  
Christoph G. W. Gertzen ◽  
Astrid Hoeppner ◽  
Nicholas Holzscheck ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Active Sites ◽  
Biological Processes ◽  
Variable Regions ◽  
Core Domain ◽  
Enzyme Superfamily ◽  
Ignicoccus Hospitalis ◽  
Enzyme Families ◽  
And Function ◽  
Structural Alignments

AbstractThe metallo-β-lactamase fold is an ancient protein structure present in numerous enzyme families responsible for diverse biological processes. The crystal structure of the hyperthermostable crenarchaeal enzyme Igni18 from Ignicoccus hospitalis was solved at 2.3 Å and could resemble a possible first archetype of a multifunctional metallo-β-lactamase. Ancestral enzymes at the evolutionary origin are believed to be promiscuous all-rounders. Consistently, Igni18´s activity can be cofactor-dependently directed from β-lactamase to lactonase, lipase, phosphodiesterase, phosphotriesterase or phospholipase. Its core-domain is highly conserved within metallo-β-lactamases from Bacteria, Archaea and Eukarya and gives insights into evolution and function of enzymes from this superfamily. Structural alignments with diverse metallo-β-lactamase-fold-containing enzymes allowed the identification of Protein Variable Regions accounting for modulation of activity, specificity and oligomerization patterns. Docking of different substrates within the active sites revealed the basis for the crucial cofactor dependency of this enzyme superfamily.

scholarly journals The crystal structure of KSHV ORF57 reveals dimeric active sites important for protein stability and function

2018 ◽  
Vol 14 (8) ◽  
pp. e1007232 ◽  
Author(s):  
Fei Yuan ◽  
Zeng-Qiang Gao ◽  
Vladimir Majerciak ◽  
Lei Bai ◽  
Meng-Lu Hu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Stability ◽  
Active Sites ◽  
And Function

The Crystal Structure ofBacillus cereusPhosphonoacetaldehyde Hydrolase:  Insight into Catalysis of Phosphorus Bond Cleavage and Catalytic Diversification within the HAD Enzyme Superfamily†,‡

Biochemistry ◽  
2000 ◽  
Vol 39 (34) ◽  
pp. 10385-10396 ◽  
Author(s):  
Marc C. Morais ◽  
Wenhai Zhang ◽  
Angela S. Baker ◽  
Guofeng Zhang ◽  
Debra Dunaway-Mariano ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Bond Cleavage ◽  
Enzyme Superfamily ◽  
Insight Into

scholarly journals Crystal Structure ofDeinococcus radioduransRecQ Helicase Catalytic Core Domain: The Interdomain Flexibility

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sheng-Chia Chen ◽  
Chi-Hung Huang ◽  
Chia Shin Yang ◽  
Tzong-Der Way ◽  
Ming-Chung Chang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Deinococcus Radiodurans ◽  
Domain Architecture ◽  
Genome Integrity ◽  
Catalytic Core Domain ◽  
Catalytic Core ◽  
Core Domain ◽  
Winged Helix ◽  
Dna Helicases ◽  
E Coli

RecQ DNA helicases are key enzymes in the maintenance of genome integrity, and they have functions in DNA replication, recombination, and repair. In contrast to most RecQs, RecQ fromDeinococcus radiodurans(DrRecQ) possesses an unusual domain architecture that is crucial for its remarkable ability to repair DNA. Here, we determined the crystal structures of the DrRecQ helicase catalytic core and its ADP-bound form, revealing interdomain flexibility in its first RecA-like and winged-helix (WH) domains. Additionally, the WH domain of DrRecQ is positioned in a different orientation from that of theE. coliRecQ (EcRecQ). These results suggest that the orientation of the protein during DNA-binding is significantly different when comparing DrRecQ and EcRecQ.

scholarly journals Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

2013 ◽  
Vol 31 (9) ◽  
pp. 1231-1238 ◽  
Author(s):  
Lindsey N. Micel ◽  
John J. Tentler ◽  
Peter G. Smith ◽  
Gail S. Eckhardt
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Regulation ◽  
Ubiquitin Chain ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Enzyme Families ◽  
And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

scholarly journals Crystal Structure of African Swine Fever Virus pS273R Protease and Implications for Inhibitor Design

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Guobang Li ◽  
Xiaoxia Liu ◽  
Mengyuan Yang ◽  
Guangshun Zhang ◽  
Zhengyang Wang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Structural Information ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Hydrolytic Activity ◽  
Viral Disease ◽  
Fever Virus ◽  
Dna Virus ◽  
Core Domain ◽  
The Core

ABSTRACT African swine fever (ASF) is a highly contagious hemorrhagic viral disease of domestic and wild pigs that is responsible for serious economic and production losses. It is caused by the African swine fever virus (ASFV), a large and complex icosahedral DNA virus of the Asfarviridae family. Currently, there is no effective treatment or approved vaccine against the ASFV. pS273R, a specific SUMO-1 cysteine protease, catalyzes the maturation of the pp220 and pp62 polyprotein precursors into core-shell proteins. Here, we present the crystal structure of the ASFV pS273R protease at a resolution of 2.3 Å. The overall structure of the pS273R protease is represented by two domains named the “core domain” and the N-terminal “arm domain.” The “arm domain” contains the residues from M1 to N83, and the “core domain” contains the residues from N84 to A273. A structure analysis reveals that the “core domain” shares a high degree of structural similarity with chlamydial deubiquitinating enzyme, sentrin-specific protease, and adenovirus protease, while the “arm domain” is unique to ASFV. Further, experiments indicated that the “arm domain” plays an important role in maintaining the enzyme activity of ASFV pS273R. Moreover, based on the structural information of pS273R, we designed and synthesized several peptidomimetic aldehyde compounds at a submolar 50% inhibitory concentration, which paves the way for the design of inhibitors to target this severe pathogen. IMPORTANCE African swine fever virus, a large and complex icosahedral DNA virus, causes a deadly infection in domestic pigs. In addition to Africa and Europe, countries in Asia, including China, Vietnam, and Mongolia, were negatively affected by the hazards posed by ASFV outbreaks in 2018 and 2019, at which time more than 30 million pigs were culled. Until now, there has been no vaccine for protection against ASFV infection or effective treatments to cure ASF. Here, we solved the high-resolution crystal structure of the ASFV pS273R protease. The pS273R protease has a two-domain structure that distinguishes it from other members of the SUMO protease family, while the unique “arm domain” has been proven to be essential for its hydrolytic activity. Moreover, the peptidomimetic aldehyde compounds designed to target the substrate binding pocket exert prominent inhibitory effects and can thus be used in a potential lead for anti-ASFV drug development.

scholarly journals New gene discoveries in skeletal diseases with short stature

2021 ◽  
Author(s):  
Alice Costantini ◽  
Mari H Muurinen ◽  
Outi Mäkitie
Keyword(s):  
Short Stature ◽  
Molecular Mechanisms ◽  
Bone Growth ◽  
Massively Parallel Sequencing ◽  
Matrix Composition ◽  
Biological Processes ◽  
Novel Gene ◽  
Genetic Mechanisms ◽  
New Gene ◽  
And Function

In the last decade, the widespread use of massively-parallel sequencing has considerably boosted the number of novel gene discoveries in monogenic skeletal diseases with short stature. Defects in genes playing a role in the maintenance and function of the growth plate, the site of longitudinal bone growth, are a well-known cause of skeletal diseases with short stature. However, several genes involved in extracellular matrix composition or maintenance as well as genes partaking in various biological processes have also been characterized. This review aims to describe the latest genetic findings in spondyloepiphyseal and spondyloepimetaphyseal dysplasias and in some monogenic forms of isolated short stature. Strategies on how to successfully characterize novel skeletal phenotypes with short stature and genetic approaches to detect and validate novel gene-disease correlations will be discussed in detail. Finally, novel genetic mechanisms in the field of skeletal diseases, including variants affecting miRNAs and disrupting the chromatin structure, will be described. In summary, we discuss the latest gene discoveries underlying skeletal diseases with short stature and emphasize the importance of characterizing novel molecular mechanisms for genetic counseling, optimal management of the disease and for therapeutic innovations.

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