Article
Chemistry, Medicinal
Martyn Frederickson, Irwin R. Selvam, Dimitrios Evangelopoulos, Kirsty J. McLean, Mona M. Katariya, Richard B. Tunnicliffe, Bethany Campbell, Madeline E. Kavanagh, Sitthivut Charoensutthivarakul, Richard T. Blankley, Colin W. Levy, Luiz Pedro S. de Carvalho, David Leys, Andrew W. Munro, Anthony G. Coyne, Chris Abell
Summary: A novel strategy combining X-ray crystallographic screening with phenotypic screening is described for hit generation against promising tuberculosis (TB) targets. This method provides validation of target engagement and determination of in vitro activity. The utility of this approach is demonstrated through the screening against CYP121A1, a validated drug discovery target for TB. Several compounds showed promising activity against Mycobacterium tuberculosis strain H37Rv, and structure-based design resulted in analogues with pan-assay activity. This study highlights the importance of developing new drugs for combating drug resistance in TB.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Rebecca K. Donegan, Yibo Fu, Jacqueline Copeland, Stanzin Idga, Gabriel Brown, Owen F. Hale, Avishek Mitra, Hui Yang, Harry A. Dailey, Michael Niederweis, Paras Jain, Amit R. Reddi
Summary: This study found that Mycobacterium tuberculosis utilizes endogenous and exogenous heme differently, and targeting heme synthesis may be an effective therapeutic strategy to treat mycobacterial infections.
MICROBIOLOGY SPECTRUM
(2022)
Article
Biochemistry & Molecular Biology
Hyun-Jong Eun, Jooyeon Lee, Su-Jin Kang, Bong-Jin Lee
Summary: Toxin and Antitoxin systems are crucial for bacterial survival against harsh environments like antibiotic treatments, with the VapBC system being the most abundant among them in Mycobacterium tuberculosis. The VapBC43 system, related to vancomycin treatment response, features a structure where a single VapB43 molecule binds to a VapC43 dimer. Despite lacking conserved acidic residues, VapC43 exhibits ribonuclease activity, and its structural information may aid in developing inhibitors for use as adjuvants in vancomycin therapy against M. tuberculosis.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Do-Hee Kim, Youngseo Na, Heesun Chang, Jun-Hyuk Boo, Sung-Min Kang, Chenglong Jin, Su-Jin Kang, Su Yeon Lee, Bong-Jin Lee
Summary: Polyketide metabolism-associated proteins in Mycobacterium tuberculosis are crucial for the survival of the bacterium, making them potential drug targets for tuberculosis treatment. This study focuses on the structural and functional characterization of a novel ribonuclease protein, Rv1546, which belongs to the steroidogenic acute regulatory protein-related lipid-transfer (START) domain superfamily. The crystal structure of Rv1546 in a V-shaped dimer is determined, and it forms a helix-grip fold through three-dimensional domain swapping. Site-directed mutagenesis and ribonuclease activity assays identify important catalytic sites of Rv1546. Overall, these findings provide new insights into the potential of Rv1546 as a drug target for tuberculosis treatment.
Article
Multidisciplinary Sciences
Luke E. Formosa, Shadi Maghool, Alice J. Sharpe, Boris Reljic, Linden Muellner-Wong, David A. Stroud, Michael T. Ryan, Megan J. Maher
Summary: COA7 is a crucial assembly factor for the biogenesis of mitochondrial complex IV. It interacts with SCO1 and SCO2 to catalyze copper relay and reduction of disulfide bonds, which are important for complex IV assembly.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Ramsay Macdonald, Brendan J. Mahoney, Jess Soule, Andrew K. Goring, Jordan Ford, Joseph A. Loo, Duilio Cascio, Robert T. Clubb
Summary: Streptococcus pyogenes uses the Shr receptor to capture hemoglobin and acquire its iron-laden heme molecules. Through a cap and release mechanism facilitated by the HID1 and HID2 domains, Shr preferentially recognizes heme-loaded forms of hemoglobin and transfers the heme to NEAT domains for iron acquisition. These receptor dynamics maximize heme scavenging efficiency by selectively targeting heme-loaded forms of hemoglobin.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Multidisciplinary
Mohammed Ahmad, Bhavya Jha, Sucharita Bose, Satish Tiwari, Abhisek Dwivedy, Deepshikha Kar, Ravikant Pal, Richard Mariadasse, Tanya Parish, Jeyaraman Jeyakanthan, Kutti R. Vinothkumar, Bichitra Kumar Biswal
Summary: This study presents the structural snapshots of Mycobacterium tuberculosis enolase as it catalyzes the conversion of PEP to 2PG. The researchers observed a novel alternate conformation of 2PG that likely facilitates its dissociation from the active site, and this conformation is different from the widely reported canonical conformation. Molecular dynamics studies and binding free energy calculations support the idea that the alternate conformation of 2PG affects metal ion coordination and hydrogen-bonding interactions, leading to increased flexibility of the active-site loops and aiding product release.
Article
Biochemistry & Molecular Biology
Cory L. Brooks, David A. Ostrov, Nicholas C. Schumann, Schuchi Kakkad, Danmeng Li, Karla Pena, Brady Paul Williams, Nathan E. Goldfarb
Summary: This study presents the crystal structure of the apo form of the hydrolase Hip1, revealing insights into the active site architecture of this drug target. By co-crystallizing Hip1 with the irreversible serine protease inhibitor AEBSF, the researchers discovered a mechanism for the conversion of the enzyme to an anhydro form. They also provide a comparative analysis of the structures of anhydrohip1 and Hip1, propose a mechanism for ligand-induced conformational changes, and expand upon the putative lipid binding pocket in the enzyme. These findings are valuable for the structure-based drug design of novel therapeutics targeting Hip1 in M. tuberculosis.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Amna Ghith, John B. Bruning, Stephen G. Bell
Summary: The CYP124 and CYP142 families of bacterial cytochrome P450 monooxygenases catalyze the oxidation of methyl branched lipids, including cholesterol, and supplement the CYP125 family of P450 enzymes in the same bacteria. The substrate binding and catalytic activity of the Mycobacterium marinum enzymes, MmarCYP124A1 and CYP142A3, were investigated with various cholesterol analogs with modifications on the A and B rings of the steroid.
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Shruti Chatterjee, Shankar V. Kundapura, Aditya J. Basak, Debangshu Mukherjee, Sagarika Dash, Namrata Ganguli, Amit K. Das, Gayatri Mukherjee, Dibyendu Samanta, Udupi A. Ramagopal
Summary: Tuberculosis is a disease caused by Mycobacterium tuberculosis, primarily transmitted through inhaling droplets from infected individuals. Mycobacteria use pathogen-associated molecular patterns (PAMPs) on their surface to enter alveolar macrophages by recognizing pattern recognition receptors on host cells. One important PAMP is the 19 kDa surface antigen LpqH, which plays a critical role in host-pathogen interactions and immune regulation. This study presents the crystal structure of non-acylated LpqH and demonstrates its functionality in inducing apoptosis in human monocytic cell line THP-1. Conservation analysis reveals a patch of conserved residues on the protein surface, potentially involved in binding partner recognition during host-pathogen interaction.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Sakiko Nakatsuji, Kenji Okumura, Ryuichi Takase, Daisuke Watanabe, Bunzo Mikami, Wataru Hashimoto
Summary: This study provides a detailed analysis of the structure and function of bacterial EfeB and EfeO. The crystal structures of EfeB and EfeO(I) were determined, revealing the presence of a heme molecule involved in oxidase activity in EfeB, and the connection of two domains in EfeO(I) by a short loop. A zinc ion was found to bind to specific residues in the C-terminal domain of EfeO(I).
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
William Richardson, Gyun Won Kang, Hee Joong Lee, Kang Mu Kwon, Saron Kim, Hyo Jung Kim
Summary: Transcription factors play a crucial role in gene expression, but the exact mechanisms of their interactions with DNA are still unclear. The structural examination of Mycobacterium tuberculosis HigA2 reveals insights into how it binds to the toxin and DNA, as well as the influence of structural domains on these interactions. The flexible alignment of the HTH motif suggests a potential structural rearrangement for interaction with DNA.
Article
Chemistry, Multidisciplinary
Abigail R. Orun, Ethan T. Shields, Sara Dmytriw, Ananya Vajapayajula, Caroline K. Slaughter, Christopher D. Snow
Summary: Researchers have designed isoreticular cocrystals as scaffolds for DNA-binding molecules. These cocrystals have tunable DNA-DNA junctions and can accommodate different guest molecules during crystallization. The design principles can be applied to existing cocrystals to develop programmable scaffolds for DNA-binding molecules.
Article
Biochemistry & Molecular Biology
Suraj Kumar Mandal, Shankar Prasad Kanaujia
Summary: The redox property of iron makes it essential for enzymes in metabolic processes. Bacterial pathogens like Mycobacterium tuberculosis can secrete siderophore molecules to capture the iron from the human host. The crystal structure of MhuP, a heme uptake protein in M. tuberculosis, has been reported, indicating its role in the transient transport of heme via the DppABCD transport system.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Review
Pharmacology & Pharmacy
Jiaxing Wang, Duane D. Miller, Wei Li
Summary: This review summarizes the crystal structures of tubulin in complexes with various CBSIs, aiming to facilitate the discovery of new generations of tubulin inhibitors.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)