scholarly journals Solvation dynamics-powered structure and function of multi-molecular cellular systems exemplified by non-equilibrium cereblon-degrader-CK1α ternary complex formation

2021 ◽  
Author(s):  
Hongbin Wan ◽  
Vibhas Aravamuthan ◽  
Sarah Williams ◽  
Charles Wartchow ◽  
Jose Duca ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Rate Constant ◽  
Surface Composition ◽  
Substrate Binding ◽  
Structure And Function ◽  
Enzyme Activation ◽  
Cellular Systems ◽  
State Transitions ◽  
Solvation Dynamics ◽  
And Function

Cellular functions are executed via a form of analog computing that is based on the switchable covalent and non-covalent states of multi-molecular fluxes (i.e., time-dependent species/state concentrations) operating in the non-linear dynamics regime. We and others have proposed that the non-covalent states and state transitions of aqueous fluxes are powered principally by the storage and release of potential energy to/from the anisotropic H-bond network of solvating water (which we refer to as the 'solvation field'), which is a key tenet of a first principles theory on cellular structure and function (called Biodynamics) that we outlined previously. This energy is reflected in water occupancy as a function of solute surface position, which can be probed computationally using WATMD software. In our previous work, we used this approach to deduce the structural dynamics of the COVID main protease, including substrate binding-induced enzyme activation and dimerization, and product release-induced dimer dissociation. Here, we examine: 1) The general relationships between surface composition/topology and solvation field properties for both high and low molecular weight (HMW and LMW) solutes. 2) The general means by which structural dynamics are powered by solvation free energy, which we exemplify via binding between the E3 ligase CUL4A/RBX1/DDB1/CRBN, LMW degraders, and substrates. We propose that degraders organize the substrate binding surface of cereblon toward complementarity with native and neo substrates, thereby speeding the association rate constant and incrementally slowing the dissociation rate constant. 3) Structure-activity relationships (SAR) based on complementarity between the solvation fields of cognate protein-ligand partners exemplified via LMW degraders.

Chitosanase from Streptomyces sp. strain N174: a comparative review of its structure and function

1997 ◽  
Vol 75 (6) ◽  
pp. 687-696 ◽  
Author(s):  
Tamo Fukamizo ◽  
Ryszard Brzezinski
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Substrate Binding ◽  
Structure And Function ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Streptomyces Sp ◽  
Binding Cleft ◽  
And Function

Novel information on the structure and function of chitosanase, which hydrolyzes the beta -1,4-glycosidic linkage of chitosan, has accumulated in recent years. The cloning of the chitosanase gene from Streptomyces sp. strain N174 and the establishment of an efficient expression system using Streptomyces lividans TK24 have contributed to these advances. Amino acid sequence comparisons of the chitosanases that have been sequenced to date revealed a significant homology in the N-terminal module. From energy minimization based on the X-ray crystal structure of Streptomyces sp. strain N174 chitosanase, the substrate binding cleft of this enzyme was estimated to be composed of six monosaccharide binding subsites. The hydrolytic reaction takes place at the center of the binding cleft with an inverting mechanism. Site-directed mutagenesis of the carboxylic amino acid residues that are conserved revealed that Glu-22 and Asp-40 are the catalytic residues. The tryptophan residues in the chitosanase do not participate directly in the substrate binding but stabilize the protein structure by interacting with hydrophobic and carboxylic side chains of the other amino acid residues. Structural and functional similarities were found between chitosanase, barley chitinase, bacteriophage T4 lysozyme, and goose egg white lysozyme, even though these proteins share no sequence similarities. This information can be helpful for the design of new chitinolytic enzymes that can be applied to carbohydrate engineering, biological control of phytopathogens, and other fields including chitinous polysaccharide degradation. Key words: chitosanase, amino acid sequence, overexpression system, reaction mechanism, site-directed mutagenesis.

scholarly journals The structure and function of centriolar rootlets

2021 ◽  
Vol 134 (16) ◽  
Author(s):  
Robert Mahen
Keyword(s):  
Cellular Function ◽  
Structure And Function ◽  
Cellular Systems ◽  
Macromolecular Assemblies ◽  
Cellular Processes ◽  
Holistic Understanding ◽  
Eukaryotic Organisms ◽  
And Function ◽  
Knockout Animals

ABSTRACT To gain a holistic understanding of cellular function, we must understand not just the role of individual organelles, but also how multiple macromolecular assemblies function collectively. Centrioles produce fundamental cellular processes through their ability to organise cytoskeletal fibres. In addition to nucleating microtubules, centrioles form lesser-known polymers, termed rootlets. Rootlets were identified over a 100 years ago and have been documented morphologically since by electron microscopy in different eukaryotic organisms. Rootlet-knockout animals have been created in various systems, providing insight into their physiological functions. However, the precise structure and function of rootlets is still enigmatic. Here, I consider common themes of rootlet function and assembly across diverse cellular systems. I suggest that the capability of rootlets to form physical links from centrioles to other cellular structures is a general principle unifying their functions in diverse cells and serves as an example of how cellular function arises from collective organellar activity.

Synaptopathy: dysfunction of synaptic function?

2010 ◽  
Vol 38 (2) ◽  
pp. 443-444 ◽  
Author(s):  
Nils Brose ◽  
Vincent O'Connor ◽  
Paul Skehel
Keyword(s):  
Animal Experimentation ◽  
Structure And Function ◽  
Synaptic Function ◽  
Cellular Systems ◽  
Brain Diseases ◽  
Psychiatric Disease ◽  
Synaptic Dysfunction ◽  
A Value ◽  
Synaptic Structure ◽  
And Function

Synaptopathy is an increasingly popular term used to define key features of neurodegenerative and psychiatric disease. It implies that disruptions in synaptic structure and function are potentially the major determinant of such brain diseases. The Synaptopathies: Dysfunction of Synaptic Function Biochemical Society Focused Meeting brought together several invited speakers, supplemented with short communications from young scientists, who addressed this possibility. The talks spanned the full gamut of approaches that brought molecular, cellular, systems and whole-animal experimentation together to address how fundamental synaptic biology was increasingly informing on dysfunction in disease. The disease and models thereof discussed included Alzheimer's disease, prions, Huntington's disease, Parkinson's disease, schizophrenia and autism. The audience were asked to reflect on whether synaptopathy, although attractive and conceptually useful, provided a significant explanation as the cause of these major diseases. The breadth of the meeting reinforced the complexity of these brain diseases, supported the significance of synaptic dysfunction in disease, but left open the issue as to whether the prime cause of these disorders could be resolved as simple synaptic dysfunction. Thus, despite revealing a value of synaptopathy, further investigation will be required to reveal its balance in the cause and effect in each of the major brain diseases.

Structure and Function of the Xenobiotic Substrate-Binding Site and Location of a Potential Non-Substrate-Binding Site in a Class π GlutathioneS-Transferase†,‡

Biochemistry ◽  
1997 ◽  
Vol 36 (32) ◽  
pp. 9690-9702 ◽  
Author(s):  
Xinhua Ji ◽  
Maria Tordova ◽  
Rosemary O'Donnell ◽  
James F. Parsons ◽  
Janet B. Hayden ◽  
...  
Keyword(s):  
Binding Site ◽  
Substrate Binding ◽  
Structure And Function ◽  
Substrate Binding Site ◽  
And Function

Structure and Function of Residue 104 and Water Molecules in the Xenobiotic Substrate-Binding Site in Human GlutathioneS-Transferase P1-1†,‡

Biochemistry ◽  
1999 ◽  
Vol 38 (32) ◽  
pp. 10231-10238 ◽  
Author(s):  
Xinhua Ji ◽  
Jaroslaw Blaszczyk ◽  
Bing Xiao ◽  
Rosemary O'Donnell ◽  
Xun Hu ◽  
...  
Keyword(s):  
Binding Site ◽  
Substrate Binding ◽  
Structure And Function ◽  
Water Molecules ◽  
Substrate Binding Site ◽  
And Function

From protoplasmic theory to cellular systems biology: a 150-year reflection

2010 ◽  
Vol 298 (6) ◽  
pp. C1280-C1290 ◽  
Author(s):  
G. Rickey Welch ◽  
James S. Clegg
Keyword(s):  
Systems Biology ◽  
Cell Biology ◽  
Cell Structure ◽  
Structure And Function ◽  
Cellular Systems ◽  
Controversial Issues ◽  
Cell Theory ◽  
History Of ◽  
And Function

Present-day cellular systems biology is producing data on an unprecedented scale. This field has generated a renewed interest in the holistic, “system” character of cell structure-and-function. Underlying the data deluge, however, there is a clear and present need for a historical foundation. The origin of the “system” view of the cell dates to the birth of the protoplasm concept. The 150-year history of the role of “protoplasm” in cell biology is traced. It is found that the “protoplasmic theory,” not the “cell theory,” was the key 19th-century construct that drove the study of the structure-and-function of living cells and set the course for the development of modern cell biology. The evolution of the “protoplasm” picture into the 20th century is examined by looking at controversial issues along the way and culminating in the current views on the role of cytological organization in cellular activities. The relevance of the “protoplasmic theory” to 21st-century cellular systems biology is considered.

Structure and function of Caulobacter crescentus aldose–aldose oxidoreductase

2015 ◽  
Vol 472 (3) ◽  
pp. 297-307 ◽  
Author(s):  
Helena Taberman ◽  
Martina Andberg ◽  
Anu Koivula ◽  
Nina Hakulinen ◽  
Merja Penttilä ◽  
...  
Keyword(s):  
Reaction Mechanism ◽  
Crystal Structures ◽  
Molecular Basis ◽  
Caulobacter Crescentus ◽  
Substrate Binding ◽  
Structure And Function ◽  
Sugar Alcohols ◽  
And Function

We solved the crystal structures of Caulobacter crescentus aldose–aldose oxidoreductase complexed with its NADP(H) cofactor, different saccharides and sugar alcohols. The structures demonstrate the molecular basis for substrate binding and allowed us to present a reaction mechanism for the enzyme.

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