scholarly journals A Thermodynamic Analysis of the Binding Specificity between Four Human PDZ Domains and Eight Host, Viral and Designed Ligands

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1071
Author(s):  
Eva S. Cobos ◽  
Ignacio E. Sánchez ◽  
Lucía B. Chemes ◽  
Jose C. Martinez ◽  
Javier Murciano-Calles
Keyword(s):  
Thermodynamic Analysis ◽  
Pdz Domain ◽  
Binding Specificity ◽  
Binding Mode ◽  
The Other ◽  
Cell Junctions ◽  
Pdz Domains ◽  
Host Interactions ◽  
Traditional Classification ◽  
Diverse Interactions

PDZ domains are binding modules mostly involved in cell signaling and cell–cell junctions. These domains are able to recognize a wide variety of natural targets and, among the PDZ partners, viruses have been discovered to interact with their host via a PDZ domain. With such an array of relevant and diverse interactions, PDZ binding specificity has been thoroughly studied and a traditional classification has grouped PDZ domains in three major specificity classes. In this work, we have selected four human PDZ domains covering the three canonical specificity-class binding mode and a set of their corresponding binders, including host/natural, viral and designed PDZ motifs. Through calorimetric techniques, we have covered the entire cross interactions between the selected PDZ domains and partners. The results indicate a rather basic specificity in each PDZ domain, with two of the domains that bind their cognate and some non-cognate ligands and the two other domains that basically bind their cognate partners. On the other hand, the host partners mostly bind their corresponding PDZ domain and, interestingly, the viral ligands are able to bind most of the studied PDZ domains, even those not previously described. Some viruses may have evolved to use of the ability of the PDZ fold to bind multiple targets, with resulting affinities for the virus–host interactions that are, in some cases, higher than for host–host interactions.

scholarly journals Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Caterina Nardella ◽  
Lorenzo Visconti ◽  
Francesca Malagrinò ◽  
Livia Pagano ◽  
Marianna Bufano ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Viral Infections ◽  
Pdz Domain ◽  
Cell Junctions ◽  
Pdz Domains ◽  
Protein Protein Interaction ◽  
Cellular Life ◽  
Functional Features ◽  
Cellular Pathways

AbstractThe interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein–protein interaction modules, involved in several cellular pathways such as signal transduction, cell–cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo.

scholarly journals Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

2017 ◽  
Vol 114 (19) ◽  
pp. E3776-E3785 ◽  
Author(s):  
Jianchao Li ◽  
Yunyun He ◽  
Meredith L. Weck ◽  
Qing Lu ◽  
Matthew J. Tyska ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Common Property ◽  
Pdz Domain ◽  
Binding Mode ◽  
Pdz Domains ◽  
Unconventional Myosin ◽  
Binding Partners ◽  
Interaction Mode ◽  
Similar Mode ◽  
And Function

Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.

Structures and target recognition modes of PDZ domains: recurring themes and emerging pictures

2013 ◽  
Vol 455 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Fei Ye ◽  
Mingjie Zhang
Keyword(s):  
Amino Acid ◽  
Pdz Domain ◽  
Binding Mode ◽  
Structural Features ◽  
Scaffold Proteins ◽  
Amino Acid Residues ◽  
Pdz Domains ◽  
Target Proteins ◽  
Protein Protein Interaction ◽  
Target Binding

PDZ domains are highly abundant protein–protein interaction modules and are often found in multidomain scaffold proteins. PDZ-domain-containing scaffold proteins regulate multiple biological processes, including trafficking and clustering receptors and ion channels at defined membrane regions, organizing and targeting signalling complexes at specific cellular compartments, interfacing cytoskeletal structures with membranes, and maintaining various cellular structures. PDZ domains, each with ~90-amino-acid residues folding into a highly similar structure, are best known to bind to short C-terminal tail peptides of their target proteins. A series of recent studies have revealed that, in addition to the canonical target-binding mode, many PDZ–target interactions involve amino acid residues beyond the regular PDZ domain fold, which we refer to as extensions. Such extension sequences often form an integral structural and functional unit with the attached PDZ domain, which is defined as a PDZ supramodule. Correspondingly, PDZ-domain-binding sequences from target proteins are frequently found to require extension sequences beyond canonical short C-terminal tail peptides. Formation of PDZ supramodules not only affords necessary binding specificities and affinities demanded by physiological functions of PDZ domain targets, but also provides regulatory switches to be built in the PDZ–target interactions. At the 20th anniversary of the discovery of PDZ domain proteins, we try to summarize structural features and target-binding properties of such PDZ supramodules emerging from studies in recent years.

scholarly journals Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Lin ◽  
Huang Wang ◽  
Decheng Ren ◽  
Yitian Xia ◽  
Guang He ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Vision Loss ◽  
Biochemical Characterization ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Binding Pocket ◽  
Binding Mode ◽  
Lipid Binding ◽  
Membrane Targeting ◽  
Pdz Domains

Usher syndrome (USH) is the leading cause of hereditary hearing–vision loss in humans. PDZ domain-containing 7 (PDZD7) has been reported to be a modifier of and contributor to USH. PDZD7 co-localizes with USH2 proteins in the inner ear hair cells and is essential for ankle-link formation and stereocilia development. PDZD7 contains three PDZ domains and a low-complexity region between the last two PDZ domains, which has been overlooked in the previous studies. Here we characterized a well-folded harmonin homology domain (HHD) from the middle region and solved the PDZD7 HHD structure at the resolution of 1.49 Å. PDZD7 HHD adopts the same five-helix fold as other HHDs found in Harmonin and Whirlin; however, in PDZD7 HHD, a unique α1N helix occupies the canonical binding pocket, suggesting a distinct binding mode. Moreover, we found that the PDZD7 HHD domain can bind lipid and mediate the localization of PDZD7 to the plasma membrane in HEK293T cells. Intriguingly, a hearing-loss mutation at the N-terminal extension region of the HHD can disrupt the lipid-binding ability of PDZD7 HHD, suggesting that HHD-mediated membrane targeting is required for the hearing process. This structural and biochemical characterization of the PDZD7 HHD region provides mechanistic explanations for human deafness-causing mutations in PDZD7. Furthermore, this structure will also facilitate biochemical and functional studies of other HHDs.

Thermodynamic Analysis of a Hydrophobic Binding Site:  Probing the PDZ Domain with Nonproteinogenic Peptide Ligands

2004 ◽  
Vol 6 (20) ◽  
pp. 3429-3432 ◽  
Author(s):  
Dorina Saro ◽  
Edvin Klosi ◽  
Azrael Paredes ◽  
Mark R. Spaller
Keyword(s):  
Binding Site ◽  
Thermodynamic Analysis ◽  
Pdz Domain ◽  
Peptide Ligands ◽  
Hydrophobic Binding

scholarly journals Role of the PDZ Domains in Escherichia coli DegP Protein

2007 ◽  
Vol 189 (8) ◽  
pp. 3176-3186 ◽  
Author(s):  
Jack Iwanczyk ◽  
Daniela Damjanovic ◽  
Joel Kooistra ◽  
Vivian Leong ◽  
Ahmad Jomaa ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protease Activity ◽  
Pdz Domain ◽  
Structural Features ◽  
Periplasmic Protein ◽  
Pdz Domains ◽  
Protease Domain ◽  
Interaction Domains ◽  
And Function

ABSTRACT PDZ domains are modular protein interaction domains that are present in metazoans and bacteria. These domains possess unique structural features that allow them to interact with the C-terminal residues of their ligands. The Escherichia coli essential periplasmic protein DegP contains two PDZ domains attached to the C-terminal end of the protease domain. In this study we examined the role of each PDZ domain in the protease and chaperone activities of this protein. Specifically, DegP mutants with either one or both PDZ domains deleted were generated and tested to determine their protease and chaperone activities, as well as their abilities to sequester unfolded substrates. We found that the PDZ domains in DegP have different roles; the PDZ1 domain is essential for protease activity and is responsible for recognizing and sequestering unfolded substrates through C-terminal tags, whereas the PDZ2 domain is mostly involved in maintaining the hexameric cage of DegP. Interestingly, neither of the PDZ domains was required for the chaperone activity of DegP. In addition, we found that the loops connecting the protease domain to PDZ1 and connecting PDZ1 to PDZ2 are also essential for the protease activity of the hexameric DegP protein. New insights into the roles of the PDZ domains in the structure and function of DegP are provided. These results imply that DegP recognizes substrate molecules targeted for degradation and substrate molecules targeted for refolding in different manners and suggest that the substrate recognition mechanisms may play a role in the protease-chaperone switch, dictating whether the substrate is degraded or refolded.

Protein environment affects the water–tryptophan binding mode. MD, QM/MM, and NMR studies of engrailed homeodomain mutants

2018 ◽  
Vol 20 (18) ◽  
pp. 12664-12677 ◽  
Author(s):  
Nad'a Špačková ◽  
Zuzana Trošanová ◽  
Filip Šebesta ◽  
Séverine Jansen ◽  
Jaroslav V. Burda ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lone Pair ◽  
Binding Mode ◽  
The Other ◽  
Water Molecules ◽  
Interaction Type ◽  
Nmr Studies ◽  
Engrailed Homeodomain ◽  
The One ◽  
Protein Environment

Water molecules can interact with the π-face of tryptophan either forming an O–H⋯π hydrogen bond or by a lone-pair⋯π interaction. Surrounding amino acids can favor the one or the other interaction type.

scholarly journals Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 870
Author(s):  
Joanna Matysiak ◽  
Alicja Skrzypek ◽  
Monika Karpińska ◽  
Kamila Czarnecka ◽  
Paweł Szymański ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Selectivity ◽  
Antioxidant Properties ◽  
Binding Mode ◽  
Biological Evaluation ◽  
The Other ◽  
Docking Simulations ◽  
Sar Studies ◽  
Structure Activity

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80–90 nM) AChE and moderate (IC50 5–0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1–42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

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