-
Nature Reviews. Drug Discovery Jan 2022Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins... (Review)
Review
Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.
Topics: Animals; Drug Discovery; Humans; Integrins; Protein Binding; Small Molecule Libraries
PubMed: 34535788
DOI: 10.1038/s41573-021-00284-4 -
Iranian Biomedical Journal Jul 2021Viruses are obligatory intracellular parasites that use cell proteins to take the control of the cell functions in order to accomplish their life cycle. Studying the... (Review)
Review
Viruses are obligatory intracellular parasites that use cell proteins to take the control of the cell functions in order to accomplish their life cycle. Studying the viral-host interactions would increase our knowledge of the viral biology and mechanisms of pathogenesis. Studies on pathogenesis mechanisms of lyssaviruses, which are the causative agents of rabies, have revealed some important host protein partners for viral proteins, especially for most studied species, i.e. Rabies virus. In this review article, the key physical lyssavirus-host protein interactions, their contributions to rabies infection, and their exploitation are discussed to improve the knowledge about rabies pathogenesis.
Topics: Animals; Host Microbial Interactions; Humans; Lyssavirus; Phagocytosis; Protein Binding; Rabies; Rabies virus
PubMed: 34217155
DOI: 10.52547/ibj.25.4.226 -
International Journal of Molecular... Jun 2023Protein self-association is a biologically remarkable event that involves and affects the structural and functional properties of proteins [...].
Protein self-association is a biologically remarkable event that involves and affects the structural and functional properties of proteins [...].
Topics: Proteins; Protein Binding; Protein Multimerization; Protein Conformation
PubMed: 37445826
DOI: 10.3390/ijms241310648 -
ELife Aug 2020Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we...
Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.
Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cullin Proteins; Cyclin-Dependent Kinases; Cyclins; DNA-Binding Proteins; Female; Humans; Male; Protein Binding; Proteolysis
PubMed: 32804079
DOI: 10.7554/eLife.59994 -
Current Issues in Molecular Biology 2021Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma... (Review)
Review
Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma membrane. This entry event is mediated by a set of essential entry glycoproteins, including glycoprotein D (gD), gHgL, and gB. gHgL and gB are conserved among herpesviruses, but gD is unique to the alphaherpesviruses and is not encoded by all alphaherpesviruses. gD is a receptor-binding protein, the heterodimer gHgL serves as a fusion regulator, and gB is a class III viral fusion protein. Sequential interactions among these glycoproteins are thought to trigger the virus to fuse at the right place and time. Structural studies of these glycoproteins from multiple alphaherpesviruses has enabled the design and interpretation of functional studies. The structures of gD in a receptor- bound and in an unliganded form reveal a conformational change in the C terminus of the gD ectodomain upon receptor binding that may serve as a signal for fusion. By mapping neutralizing antibodies to the gHgL structures and constructing interspecies chimeric forms of gHgL, interaction sites for both gD and gB on gHgL have been proposed. A comparison of the post fusion structure of gB and an alternative conformation of gB visualized using cryo- electron tomography suggests that gB undergoes substantial refolding to execute membrane fusion. Although these structures have provided excellent insights into the entry mechanism, many questions remain about how these viruses coordinate the interactions and conformational changes required for entry.
Topics: Alphaherpesvirinae; Animals; Cell Membrane; Glycoproteins; Herpesviridae Infections; Humans; Protein Binding; Protein Conformation; Virus Internalization
PubMed: 32764159
DOI: 10.21775/cimb.041.063 -
Briefings in Bioinformatics Jul 2022Proteins are capable of highly specific interactions and are responsible for a wide range of functions, making them attractive in the pursuit of new therapeutic options.... (Review)
Review
Proteins are capable of highly specific interactions and are responsible for a wide range of functions, making them attractive in the pursuit of new therapeutic options. Previous studies focusing on overall geometry of protein-protein interfaces, however, concluded that PPI interfaces were generally flat. More recently, this idea has been challenged by their structural and thermodynamic characterisation, suggesting the existence of concave binding sites that are closer in character to traditional small-molecule binding sites, rather than exhibiting complete flatness. Here, we present a large-scale analysis of binding geometry and physicochemical properties of all protein-protein interfaces available in the Protein Data Bank. In this review, we provide a comprehensive overview of the protein-protein interface landscape, including evidence that even for overall larger, more flat interfaces that utilize discontinuous interacting regions, small and potentially druggable pockets are utilized at binding sites.
Topics: Binding Sites; Databases, Protein; Protein Binding; Proteins
PubMed: 35656714
DOI: 10.1093/bib/bbac165 -
Current Opinion in Structural Biology Oct 2020Current developments in protein docking aim at improvement of applicability, accuracy and utility of modeling macromolecular complexes. The challenges include the need... (Review)
Review
Current developments in protein docking aim at improvement of applicability, accuracy and utility of modeling macromolecular complexes. The challenges include the need for greater emphasis on protein docking to molecules of different types, proper accounting for conformational flexibility upon binding, new promising methodologies based on residue co-evolution and deep learning, affinity prediction, and further development of fully automated docking servers. Importantly, new developments increasingly focus on realistic modeling of protein interactions in vivo, including crowded environment inside a cell, which involves multiple transient encounters, and propagating the system in time. This opinion paper offers the author's perspective on these challenges in structural modeling of protein interactions and the future of protein docking.
Topics: Molecular Docking Simulation; Protein Binding; Proteins
PubMed: 32836051
DOI: 10.1016/j.sbi.2020.07.001 -
Protein Science : a Publication of the... Feb 2022To expand protein's covalent bonding ability, latent bioreactive unnatural amino acids have been designed and genetically encoded into proteins, which react with... (Review)
Review
To expand protein's covalent bonding ability, latent bioreactive unnatural amino acids have been designed and genetically encoded into proteins, which react with specific natural amino acid residues through proximity-enabled bioreactivity. The resultant new covalent bonds can be selectively created within and between proteins in vitro, in cells, and in vivo. Offering diverse properties previously unattainable, these covalent linkages have been harnessed to enhance protein properties, to modulate protein function, to probe ligand-receptor binding, to identify elusive protein interactions, and to develop covalent protein drugs. Selective introduction of covalent bonds into proteins is affording novel avenues for biological studies, synthetic biology, and biotherapeutics.
Topics: Amino Acids; Ligands; Protein Binding; Protein Engineering; Proteins
PubMed: 34761448
DOI: 10.1002/pro.4228 -
International Journal of Molecular... Oct 2022With the exponential increase in publicly available protein structures, the comparison of protein binding sites naturally emerged as a scientific topic to explain... (Review)
Review
With the exponential increase in publicly available protein structures, the comparison of protein binding sites naturally emerged as a scientific topic to explain observations or generate hypotheses for ligand design, notably to predict ligand selectivity for on- and off-targets, explain polypharmacology, and design target-focused libraries. The current review summarizes the state-of-the-art computational methods applied to pocket detection and comparison as well as structural druggability estimates. The major strengths and weaknesses of current pocket descriptors, alignment methods, and similarity search algorithms are presented. Lastly, an exhaustive survey of both retrospective and prospective applications in diverse medicinal chemistry scenarios illustrates the capability of the existing methods and the hurdle that still needs to be overcome for more accurate predictions.
Topics: Ligands; Retrospective Studies; Drug Design; Proteins; Binding Sites; Protein Binding; Algorithms; Protein Conformation
PubMed: 36293316
DOI: 10.3390/ijms232012462 -
Molecules (Basel, Switzerland) Oct 2020Many biological functions of peptides are mediated through G protein-coupled receptors (GPCRs). Upon ligand binding, GPCRs undergo conformational changes that facilitate... (Review)
Review
Many biological functions of peptides are mediated through G protein-coupled receptors (GPCRs). Upon ligand binding, GPCRs undergo conformational changes that facilitate the binding and activation of multiple effectors. GPCRs regulate nearly all physiological processes and are a favorite pharmacological target. In particular, drugs are sought after that elicit the recruitment of selected effectors only (biased ligands). Understanding how ligands bind to GPCRs and which conformational changes they induce is a fundamental step toward the development of more efficient and specific drugs. Moreover, it is emerging that the dynamic of the ligand-receptor interaction contributes to the specificity of both ligand recognition and effector recruitment, an aspect that is missing in structural snapshots from crystallography. We describe here biochemical and biophysical techniques to address ligand-receptor interactions in their structural and dynamic aspects, which include mutagenesis, crosslinking, spectroscopic techniques, and mass-spectrometry profiling. With a main focus on peptide receptors, we present methods to unveil the ligand-receptor contact interface and methods that address conformational changes both in the ligand and the GPCR. The presented studies highlight a wide structural heterogeneity among peptide receptors, reveal distinct structural changes occurring during ligand binding and a surprisingly high dynamics of the ligand-GPCR complexes.
Topics: Humans; Ligands; Peptides; Protein Binding; Protein Conformation; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 33076289
DOI: 10.3390/molecules25204724