Membrane-Bound Transcription Factor Site-1 Protease in PF429242 Bound State: Computational Kinetics and Dynamics of Reversible Binding

Drug Research ◽  
2019 ◽  
Vol 69 (12) ◽  
pp. 643-649 ◽  
Author(s):  
Omotuyi I. Olaposi ◽  
Nash Oyekanmi ◽  
Ayodeji A. Ojo ◽  
Gabriel O. Eniafe
Keyword(s):  
Transcription Factor ◽  
Bound States ◽  
Homology Model ◽  
Bound State ◽  
Catalytic Triad ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Viral Glycoprotein ◽  
Reversible Binding ◽  
Membrane Bound

AbstractMembrane-bound transcription factor site-1 protease (S1P) is an emerging clinical target due to its roles in lipogenesis, lysosomal biogenesis, unfolded protein response and viral glycoprotein processing. In this study, homology model of S1P was created in order to understand the structural basis for S1P inhibition by PF429242 using molecular docking, molecular dynamics simulation and in silico kinetics studies. PF429242 was docked (GlideScorePF429242=−5.20 kcal/mol) into the catalytic triad (D218, H249 and S414) and validated (R2=0.5686). The reversible binding kinetic parameter (Koff/Kon) was estimated at=7.28E-03 M with fully bound and apo-states interspersed by 3 transient ligand-bound states with unique binding signatures; water plays a major role in PF429242 dissociation from the catalytic site. Communication between key catalytic triad residues is altered in the presence of PF429242. In apo-S1P state, S414–S307/V216-D218 is the preferred route but in PF429242-bound state, S414-S417/V216-D218 is preferred. Communication between S414 and H249 is also shortened in PF429242 bound state; here, only L410 is required unlike apo-state, which requires P418, V256 and F252. Ligand binding did not alter the communication route between S414 and H249 as both recruited D244 and G220. In conclusion, PF429242 binds tightly but reversible to S1P and the details of this interaction has been presented to guide future efforts at developing novel inhibitors. Site-1-protease; PF429242; Kon/Koff; Network analysis

scholarly journals Structural basis of αE-catenin–F-actin catch bond behavior

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Xiao-Ping Xu ◽  
Sabine Pokutta ◽  
Megan Torres ◽  
Mark F Swift ◽  
Dorit Hanein ◽  
...  
Keyword(s):  
Bound States ◽  
Mechanical Load ◽  
Optical Trap ◽  
Bound State ◽  
Actin Binding ◽  
Structural Basis ◽  
Catch Bond ◽  
Strong State ◽  
Cell Matrix ◽  
Cell Cell

Cell-cell and cell-matrix junctions transmit mechanical forces during tissue morphogenesis and homeostasis. α-Catenin links cell-cell adhesion complexes to the actin cytoskeleton, and mechanical load strengthens its binding to F-actin in a direction-sensitive manner. Specifically, optical trap experiments revealed that force promotes a transition between weak and strong actin-bound states. Here, we describe the cryo-electron microscopy structure of the F-actin-bound αE-catenin actin-binding domain, which in solution forms a five-helix bundle. In the actin-bound structure, the first helix of the bundle dissociates and the remaining four helices and connecting loops rearrange to form the interface with actin. Deletion of the first helix produces strong actin binding in the absence of force, suggesting that the actin-bound structure corresponds to the strong state. Our analysis explains how mechanical force applied to αE-catenin or its homolog vinculin favors the strongly bound state, and the dependence of catch bond strength on the direction of applied force.

scholarly journals A Comparative Study on Interactions of Antimicrobial Peptides L- and D-phenylseptin with 1,2-dimyristoyl-sn-glycero-3-phosphocholine

2019 ◽  
Vol 9 (13) ◽  
pp. 2601 ◽  
Author(s):  
Batsaikhan Mijiddorj ◽  
Yuta Matsuo ◽  
Hisako Sato ◽  
Kazuyoshi Ueda ◽  
Izuru Kawamura
Keyword(s):  
Circular Dichroism ◽  
Antimicrobial Peptides ◽  
Lipid Bilayers ◽  
Binding Constants ◽  
Bound State ◽  
Dynamics Simulation ◽  
Membrane Bound ◽  
The Difference ◽  
Α Helix ◽  
Circular Dichroïsm

L-phenylseptin (L-Phes) and D-phenylseptin (D-Phes) are amphibian antimicrobial peptides isolated from the skin secretion of Hypsiboas punctatus. In the N-termini, L-Phes and D-Phes contain three consecutive phenylalanine residues, l-Phe-l-Phe-l-Phe and l-Phe-d-Phe-l-Phe, respectively. They are known to exhibit antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Xanthomonas axonopodis pv. Glycines. However, their mechanism of action and the role of the D-amino acid residue have not been elucidated yet. In this study, the interactions of both peptides with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were investigated by means of quartz crystal microbalance, circular dichroism, vibrational circular dichroism, 31P solid-state NMR, and molecular dynamics simulation. Both peptides have similar binding constants to the DMPC lipid bilayers, in the order of 106 M−1, and form an α-helix structure in the DMPC lipid bilayers. Both the peptides induce similar changes in the dynamics of DMPC lipids. Thus, in spite of the difference in the conformations caused by the chirality at the N-terminus, the peptides showed similar behavior in the membrane-bound state, experimentally and computationally.

scholarly journals Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Rajiv K. Kar ◽  
Md. Yousuf Ansari ◽  
Priyanka Suryadevara ◽  
Bikash R. Sahoo ◽  
Ganesh C. Sahoo ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Active Site ◽  
Protein Complex ◽  
Leishmania Donovani ◽  
Homology Model ◽  
Adenosine Kinase ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Active Site Residues ◽  
Drug Candidates

Enzyme adenosine kinase is responsible for phosphorylation of adenosine to AMP and is crucial for parasites which are purine auxotrophs. The present study describes development of robust homology model ofLeishmania donovaniadenosine kinase to forecast interaction phenomenon with inhibitory molecules using structure-based drug designing strategy. Docking calculation using reported organic small molecules and natural products revealed key active site residues such as Arg131 and Asp16 for ligand binding, which is consistent with previous studies. Molecular dynamics simulation of ligand protein complex revealed the importance of hydrogen bonding with active site residues and solvent molecules, which may be crucial for successful development of drug candidates. Precise role of Phe168 residue in the active site was elucidated in this report that provided stability to ligand-protein complex via aromatic-πcontacts. Overall, the present study is believed to provide valuable information to design a new compound with improved activity for antileishmanial therapeutics development.

scholarly journals Structural Studies of the 3′,3′-cGAMP Riboswitch Induced by Cognate and Noncognate Ligands Using Molecular Dynamics Simulation

2018 ◽  
Vol 19 (11) ◽  
pp. 3527 ◽  
Author(s):  
Chaoqun Li ◽  
Xiaojia Zhao ◽  
Xiaomin Zhu ◽  
Pengtao Xie ◽  
Guangju Chen
Keyword(s):  
Molecular Dynamics ◽  
Bound States ◽  
Binding Pocket ◽  
Bound State ◽  
Structural Features ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Recognition ◽  
Compact Structure ◽  
Ligand Free

Riboswtich RNAs can control gene expression through the structural change induced by the corresponding small-molecule ligands. Molecular dynamics simulations and free energy calculations on the aptamer domain of the 3′,3′-cGAMP riboswitch in the ligand-free, cognate-bound and noncognate-bound states were performed to investigate the structural features of the 3′,3′-cGAMP riboswitch induced by the 3′,3′-cGAMP ligand and the specificity of ligand recognition. The results revealed that the aptamer of the 3′,3′-cGAMP riboswitch in the ligand-free state has a smaller binding pocket and a relatively compact structure versus that in the 3′,3′-cGAMP-bound state. The binding of the 3′,3′-cGAMP molecule to the 3′,3′-cGAMP riboswitch induces the rotation of P1 helix through the allosteric communication from the binding sites pocket containing the J1/2, J1/3 and J2/3 junction to the P1 helix. Simultaneously, these simulations also revealed that the preferential binding of the 3′,3′-cGAMP riboswitch to its cognate ligand, 3′,3′-cGAMP, over its noncognate ligand, c-di-GMP and c-di-AMP. The J1/2 junction in the 3′,3′-cGAMP riboswitch contributing to the specificity of ligand recognition have also been found.

scholarly journals Structural basis of αE-catenin–F-actin catch bond behavior

2020 ◽  
Author(s):  
Xiao-Ping Xu ◽  
Sabine Pokutta ◽  
Miguel Torres ◽  
Mark F. Swift ◽  
Dorit Hanein ◽  
...  
Keyword(s):  
Bound States ◽  
Mechanical Load ◽  
Bound State ◽  
Actin Binding ◽  
Structural Basis ◽  
Catch Bond ◽  
Bond Behavior ◽  
Cell Matrix ◽  
Actin Binding Domain ◽  
Cell Cell

ABSTRACTCell-cell and cell-matrix junctions transmit mechanical forces during tissue morphogenesis and homeostasis. α-Catenin links cell-cell adhesion complexes to the actin cytoskeleton, and mechanical load strengthens its binding to F-actin in a direction-sensitive manner. This so-called catch bond behavior is described by a model in which force promotes a transition between weak and strong actin-bound states. We describe the cryo-electron microscopy structure of the F-actin-bound αE-catenin actin-binding domain, which in solution forms a 5-helix bundle. Upon binding to actin, the first helix of the bundle dissociates and the remaining four helices and connecting loops rearrange to form the interface with actin. Deletion of the N-terminal helix produces strong actin binding in the absence of force. Our analysis explains how mechanical force applied to αE-catenin or its homolog vinculin favors the strongly bound state, and the dependence of catch bond strength on the direction of applied force.

Functional characterization and structural modelling of peptidoglycan degrading β-N-acetyl-glucosaminidase from a dental isolate of Serratia marcescens

2020 ◽  
Vol 23 ◽  
Author(s):  
Aditi Rathee ◽  
Anil Panwar ◽  
Seema Kumari ◽  
Sanjay Chhibber ◽  
Ashok Kumar
Keyword(s):  
Functional Characterization ◽  
Major Change ◽  
Crystal Form ◽  
Bound State ◽  
Dynamics Simulation ◽  
Gram Positive ◽  
Structural Cell ◽  
Stability Structure ◽  
Arginine Residues ◽  
The Stability

Introduction:: Enzymatic degradation of peptidoglycan, a structural cell wall component of Gram-positive bacteria, has attracted considerable attention being a specific target for many known antibiotics. Methods:: Peptidoglycan hydrolases are involved in bacterial lysis through peptidoglycan degradation. β-N-acetylglucosaminidase, a peptidoglycan hydrolase, acts on O-glycosidic bonds formed by N-acetylglucosamine and N-acetyl muramic acid residues of peptidoglycan. Aim of present study was to study the action of β-N-acetylglucosaminidase, on methicillin- resistant Staphylococcus aureus (MRSA) and other Gram-negative bacteria. Results:: We investigated its dynamic behaviour using molecular dynamics simulation and observed that serine and alanine residues are involved in catalytic reaction in addition to aspartic acid, histidine, lysine and arginine residues. When simulated in its bound state, the RMSD values were found lesser than crystal form in the time stamp of 1000 picoseconds revealing its stability. Structure remained stably folded over 1000 picoseconds without undergoing any major change further confirming the stability of complex. Conclusion:: It can be concluded that enzymes belonging to this category can serve as a tool in eradicating Gram-positive pathogens and associated infections.

scholarly journals Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

2021 ◽  
Vol 7 (23) ◽  
pp. eabg1483
Author(s):  
Tianlei Wen ◽  
Ziyu Wang ◽  
Xiaozhe Chen ◽  
Yue Ren ◽  
Xuhang Lu ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Bound States ◽  
Hormone Secretion ◽  
Allosteric Modulation ◽  
Full Length ◽  
Structural Basis ◽  
Endocrine Disorders ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Class C

Calcium-sensing receptor (CaSR) is a class C G protein–coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo–electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca2+ and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.

scholarly journals Bound states of a Klein–Gordon particle in the presence of a smooth potential well

2020 ◽  
Vol 35 (23) ◽  
pp. 2050140
Author(s):  
Eduardo López ◽  
Clara Rojas
Keyword(s):  
Bound States ◽  
Gordon Equation ◽  
Bound State ◽  
Potential Well ◽  
One Dimensional ◽  
Smooth Potential ◽  
Klein Gordon ◽  
The One ◽  
Potential Parameters ◽  
Klein Gordon Equation

We solve the one-dimensional time-independent Klein–Gordon equation in the presence of a smooth potential well. The bound state solutions are given in terms of the Whittaker [Formula: see text] function, and the antiparticle bound state is discussed in terms of potential parameters.

RETARDATION EFFECTS IN COVARIANT THREE-DIMENSIONAL BOUND STATE WAVE FUNCTIONS

2005 ◽  
Vol 14 (06) ◽  
pp. 931-947 ◽  
Author(s):  
F. PILOTTO ◽  
M. DILLIG
Keyword(s):  
Bound States ◽  
Three Dimensional ◽  
Bound State ◽  
Relative Energy ◽  
Wave Functions ◽  
Three Dimensions ◽  
State Wave ◽  
Scalar Diquark ◽  
Bound State Wave Function ◽  
Retardation Effects

We investigate the influence of retardation effects on covariant 3-dimensional wave functions for bound hadrons. Within a quark-(scalar) diquark representation of a baryon, the four-dimensional Bethe–Salpeter equation is solved for a 1-rank separable kernel which simulates Coulombic attraction and confinement. We project the manifestly covariant bound state wave function into three dimensions upon integrating out the non-static energy dependence and compare it with solutions of three-dimensional quasi-potential equations obtained from different kinematical projections on the relative energy variable. We find that for long-range interactions, as characteristic in QCD, retardation effects in bound states are of crucial importance.

Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations

2016 ◽  
Vol 12 (4) ◽  
pp. 1174-1182 ◽  
Author(s):  
Liang Fang ◽  
Xiaojian Wang ◽  
Meiyang Xi ◽  
Tianqi Liu ◽  
Dali Yin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Model Building ◽  
Binding Free Energy ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Selectivity ◽  
Sphingosine Kinases ◽  
Binding Free Energy Calculations

Three residues of SK1 were identified important for selective SK1 inhibitory activity via SK2 homology model building, molecular dynamics simulation, and MM-PBSA studies.

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