Abstract:
:Thermodynamics and kinetics of protein-ligand binding are both important aspects for the design of novel drug molecules. Presently, thermodynamic data are collected with isothermal titration calorimetry, while kinetic data are mostly derived from surface plasmon resonance. The new method of kinITC provides both thermodynamic and kinetic data from calorimetric titration measurements. The present study demonstrates the convenient collection of calorimetric data suitable for both thermodynamic and kinetic analysis for two series of congeneric ligands of human carbonic anhydrase II and correlates these findings with structural data obtained by macromolecular crystallography to shed light on the importance of shape complementarity for thermodynamics and kinetics governing a protein-ligand binding event. The study shows how minute chemical alterations change preferred ligand conformation and can be used to manipulate thermodynamic and kinetic signatures of binding. They give rise to the observation that analogous n-alkyl and n-alkyloxy derivatives of identical chain length swap their binding kinetic properties at unchanged binding affinity.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Glöckner S,Ngo K,Sager CP,Hüfner-Wulsdorf T,Heine A,Klebe Gdoi
10.1021/acschembio.9b00895subject
Has Abstractpub_date
2020-03-20 00:00:00pages
675-685issue
3eissn
1554-8929issn
1554-8937journal_volume
15pub_type
杂志文章abstract::Development of precision therapeutics is of immense interest, particularly as applied to the treatment of cancer. By analyzing the preferred cellular RNA targets of small molecules, we discovered that 5"-azido neomycin B binds the Drosha processing site in the microRNA (miR)-525 precursor. MiR-525 confers invasive pro...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00615
更新日期:2016-02-19 00:00:00
abstract::Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are t...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300709g
更新日期:2013-07-19 00:00:00
abstract::Light-activated protein domains provide a convenient, modular, and genetically encodable sensor for optogenetics and optobiology. Although these domains have now been deployed in numerous systems, the precise mechanism of photoactivation and the accompanying structural dynamics that modulate output domain activity rem...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00543
更新日期:2020-10-16 00:00:00
abstract::Extracellular expression of heat shock protein 90 (eHsp90) by tumor cells is correlated with malignancy. Development of small molecule probes that can detect eHsp90 in vivo may therefore have utility in the early detection of malignancy. We synthesized a cell impermeable far-red fluorophore-tagged Hsp90 inhibitor to t...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00006
更新日期:2017-04-21 00:00:00
abstract::Current therapeutic interventions for both heart disease and heart failure are largely insufficient and associated with undesired side effects. Biomedical research has emphasized the role of sarcomeric protein function for the normal performance and energy efficiency of the heart, suggesting that directly targeting th...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00908
更新日期:2021-01-15 00:00:00
abstract::To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline c...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b01125
更新日期:2019-03-15 00:00:00
abstract::A complication of diabetes is the inability of wounds to heal in diabetic patients. Diabetic wounds are refractory to healing due to the involvement of activated matrix metalloproteinases (MMPs), which remodel the tissue resulting in apoptosis. There are no readily available methods that identify active unregulated MM...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb4005468
更新日期:2014-01-17 00:00:00
abstract::The expansion of the genetic code with noncanonical amino acids (ncAA) enables the function of proteins to be tailored with high molecular precision. In this approach, the ncAA is charged to an orthogonal nonsense suppressor tRNA by an aminoacyl-tRNA-synthetase (aaRS) and incorporated into the target protein in vivo b...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb5006273
更新日期:2014-12-19 00:00:00
abstract::mRNA-based therapies and vaccines constitute a disruptive technology with the potential to revolutionize modern medicine. Chemically modified 5' cap structures have provided access to mRNAs with superior translational properties that could benefit the currently flourishing mRNA field. Prime examples of compounds that ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00864
更新日期:2021-01-13 00:00:00
abstract::The past several years have seen numerous reports of new chemical modifications for use in RNA. In addition, in that time period, we have seen the discovery of several previously unknown naturally occurring modifications that impart novel properties on the parent RNAs. In this review, we describe recent discoveries in...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb200422t
更新日期:2012-01-20 00:00:00
abstract::There is a pressing need for new molecular tools to target protein surfaces with high affinity and specificity. Here, we describe cyclic messenger RNA display with a trillion-member covalent peptide macrocycle library. Using this library, we have designed a number of high-affinity, redox-insensitive, cyclic peptides t...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb7001126
更新日期:2007-09-21 00:00:00
abstract::3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00090
更新日期:2020-04-17 00:00:00
abstract::A class of new glycan-reactive broadly neutralizing antibodies represented by PGT121, 10-1074, and PGT128 has recently been discovered that targets specific N-glycans and the peptide region around the V3 domain. However, the glycan specificity and fine epitopes of these bNAbs remain to be further defined. We report he...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00319
更新日期:2017-06-16 00:00:00
abstract::BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00058
更新日期:2020-04-17 00:00:00
abstract::Modern visualization techniques are affording a peek into complex cellular processes. A recent paper describes an automated fluorescence microscopy method to map the subcellular localization of up to 100 different proteins in the same sample. ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb600461v
更新日期:2006-12-15 00:00:00
abstract::Nature uses four methods of carbon chain elongation for the production of 2-ketoacids, fatty acids, polyketides, and isoprenoids. Using a combination of quantum mechanical (QM) modeling, protein-substrate modeling, and protein and metabolic engineering, we have engineered the enzymes involved in leucine biosynthesis f...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200313e
更新日期:2012-04-20 00:00:00
abstract::The genetic integrity of each organism depends on the faithful segregation of its genome during mitosis. To meet this challenge, a cellular surveillance mechanism, termed the spindle assembly checkpoint (SAC), evolved that monitors the correct attachment of chromosomes and blocks progression through mitosis if correct...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00121
更新日期:2015-07-17 00:00:00
abstract::C-methylation of aromatic small molecules by C-methyltransferases (C-MTs) is an important biological transformation that involves C-C bond formation using S-adenosyl-l-methionine (SAM) as the methyl donor. Here, two advances in the mechanistic understanding of C-methylation of the 8-position of coumarin substrates cat...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b01053
更新日期:2017-02-17 00:00:00
abstract::The nonheme diiron enzyme cyanobacterial aldehyde deformylating oxygenase, cADO, catalyzes the highly unusual deformylation of aliphatic aldehydes to alkanes and formate. We have determined crystal structures for the enzyme with a long-chain water-soluble aldehyde and medium-chain carboxylic acid bound to the active s...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb500343j
更新日期:2014-11-21 00:00:00
abstract::A Natural Compound Library containing myxobacterial secondary metabolites was screened in murine macrophages for novel activators of IL-1β maturation and secretion. The most potent of three hits in total was a so far undescribed metabolite, which was identified from the myxobacterium Hyalangium minutum strain Hym3. Wh...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00659
更新日期:2018-10-19 00:00:00
abstract::The Siglec family of sialic acid-binding proteins are differentially expressed on white blood cells of the immune system and represent an attractive class of targets for cell-directed therapy. Nanoparticles decorated with high-affinity Siglec ligands show promise for delivering cargo to Siglec-bearing cells, but this ...
journal_title:ACS chemical biology
pub_type: 信件
doi:10.1021/cb400125w
更新日期:2013-07-19 00:00:00
abstract::We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subuni...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00109
更新日期:2015-07-17 00:00:00
abstract::The abundant observation of chemical fragment information for molecular complexities is a major advantage of biological NMR analysis. Thus, the development of a novel technique for NMR signal assignment and metabolite identification may offer new possibilities for exploring molecular complexities. We propose a new sig...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00894
更新日期:2016-04-15 00:00:00
abstract::The publication of the first high-resolution crystal structure of a eukaryotic Cys-loop receptor, GluClα, has provided valuable structural information on this important class of ligand-gated ion channels (LGIC). However, limited functional data exist for the GluCl receptors. Before applying the structural insights fro...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb500323d
更新日期:2014-10-17 00:00:00
abstract::STAT family proteins are important mediators of cell signaling and represent therapeutic targets for the treatment of human diseases. Most STAT inhibitors target the protein-protein interaction domain, the SH2 domain, but specificity for a single STAT protein is often limited. Recently, we developed catechol bisphosph...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00137
更新日期:2019-04-19 00:00:00
abstract::Invertebrate animal models (mainly the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) are gaining momentum as screening tools in drug discovery. These organisms combine genetic amenability, low cost, and culture conditions compatible with large-scale screens. Their main advantage is to allo...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb700009m
更新日期:2007-04-24 00:00:00
abstract::Histone post-translational modifications (PTMs) are crucial for many cellular processes including mitosis, transcription, and DNA repair. The cellular readout of histone PTMs is dependent on both the chemical modification and histone site, and the array of histone PTMs on chromatin is dynamic throughout the eukaryotic...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00651
更新日期:2020-01-17 00:00:00
abstract::Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB signaling in human cells. NSC697923 and BAY 11-7082 both i...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00222
更新日期:2015-07-17 00:00:00
abstract::Our immune system constantly samples peptides found inside the body as a means to detect foreign pathogens, infected cells, and tumorous cells. T cells, which carry out the critical task of distinguishing self from nonself peptides, can only survey peptides that are presented by the major histocompatibility complex pr...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb400594q
更新日期:2013-11-15 00:00:00
abstract::Terpenes are ubiquitous natural chemicals with diverse biological functions spanning all three domains of life. In specialized metabolism, the active sites of terpene synthases (TPSs) evolve in shape and reactivity to direct the biosynthesis of a myriad of chemotypes for organismal fitness. As most terpene biosynthesi...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00539
更新日期:2015-11-20 00:00:00