Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Bartosz Trzaskowski is active.

Publication


Featured researches published by Bartosz Trzaskowski.


Current Medicinal Chemistry | 2012

Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies

Bartosz Trzaskowski; Dorota Latek; Shuguang Yuan; Umesh Ghoshdastider; Aleksander Debinski; Slawomir Filipek

G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. Biochemical and crystallographic methods together with molecular dynamics simulations and other theoretical techniques provided models of the receptor activation based on the action of so-called “molecular switches” buried in the receptor structure. They are changed by agonists but also by inverse agonists evoking an ensemble of activation states leading toward different activation pathways. Switches discovered so far include the ionic lock switch, the 3-7 lock switch, the tyrosine toggle switch linked with the nPxxy motif in TM7, and the transmission switch. The latter one was proposed instead of the tryptophan rotamer toggle switch because no change of the rotamer was observed in structures of activated receptors. The global toggle switch suggested earlier consisting of a vertical rigid motion of TM6, seems also to be implausible based on the recent crystal structures of GPCRs with agonists. Theoretical and experimental methods (crystallography, NMR, specific spectroscopic methods like FRET/BRET but also single-molecule-force-spectroscopy) are currently used to study the effect of ligands on the receptor structure, location of stable structural segments/domains of GPCRs, and to answer the still open question on how ligands are binding: either via ensemble of conformational receptor states or rather via induced fit mechanisms. On the other hand the structural investigations of homo- and heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor activation that could lead to design highly effective and selective allosteric or ago-allosteric drugs.


Nature Reviews Drug Discovery | 2009

Community-wide assessment of GPCR structure modelling and ligand docking

Mayako Michino; Enrique Abola; Charles L. Brooks; J. Scott Dixon; John Moult; Raymond C. Stevens; Arthur J. Olson; Wiktor Jurkowski; Arne Elofsson; Slawomir Filipek; Irina D. Pogozheva; Bernard Maigret; Jeremy A. Horst; Ambrish Roy; Brady Bernard; Shyamala Iyer; Yang Zhang; Ram Samudrala; Osman Ugur Sezerman; Gregory V. Nikiforovich; Christina M. Taylor; Stefano Costanzi; Y. Vorobjev; N. Bakulina; Victor V. Solovyev; Kazuhiko Kanou; Daisuke Takaya; Genki Terashi; Mayuko Takeda-Shitaka; Hideaki Umeyama

Recent breakthroughs in the determination of the crystal structures of G protein-coupled receptors (GPCRs) have provided new opportunities for structure-based drug design strategies targeting this protein family. With the aim of evaluating the current status of GPCR structure prediction and ligand docking, a community-wide, blind prediction assessment — GPCR Dock 2008 — was conducted in coordination with the publication of the crystal structure of the human adenosine A2A receptor bound to the ligand ZM241385. Twenty-nine groups submitted 206 structural models before the release of the experimental structure, which were evaluated for the accuracy of the ligand binding mode and the overall receptor model compared with the crystal structure. This analysis highlights important aspects for success and future development, such as accurate modelling of structurally divergent regions and use of additional biochemical insight such as disulphide bridges in the extracellular loops.


ACS Chemical Biology | 2012

Genetically Encoded Photo-cross-linkers Map the Binding Site of an Allosteric Drug on a G Protein-Coupled Receptor

Amy Grunbeck; Thomas Huber; Ravinder Abrol; Bartosz Trzaskowski; William A. Goddard; Thomas P. Sakmar

G protein-coupled receptors (GPCRs) are dynamic membrane proteins that bind extracellular molecules to transduce signals. Although GPCRs represent the largest class of therapeutic targets, only a small percentage of their ligand-binding sites are precisely defined. Here we describe the novel application of targeted photo-cross-linking using unnatural amino acids to obtain structural information about the allosteric binding site of a small molecule drug, the CCR5-targeted HIV-1 co-receptor blocker maraviroc.


Journal of Chemical Information and Modeling | 2012

3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP)

Jun Tan; Ravinder Abrol; Bartosz Trzaskowski; William A. Goddard

The G protein-coupled receptor (GPCR) TAS2R38 is a bitter taste receptor that can respond to bitter compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). This receptor was chosen because its four haplotypes (based on three residue site polymorphism) hTAS2R38PAV, hTAS2R38AVI, hTAS2R38AAI, and hTAS2R38PVV are known to have dramatically different responses to PTC and PROP. We aimed to identify the protein-ligand interaction features that determine whether the bitter taste signal from this receptor is sent to the cortex. To do this we predicted the 3D structures of the TAS2R38 bitter taste receptor using our new BiHelix and SuperBiHelix Monte Carlo methods (No experimental determinations of the 3D structure have been reported for any taste receptors.). We find that residue 262 (2nd position in the polymorphism) is involved in the interhelical hydrogen bond network stabilizing the GPCR structure in tasters (hTAS2R38PAV, hTAS2R38AAI, and hTAS2R38PVV), while it is not in the nontaster (hTAS2R38AVI). This suggests that the hydrogen bond interactions between TM3 and TM6 or between TM5 and TM6 may play a role in activating this GPCR. To further validate these structures, we used the DarwinDock method to predict the binding sites and 3D structures for PTC and PROP bound to hTAS2R38PAV, hTAS2R38AVI, hTAS2R38AAI, and hTAS2R38PVV, respectively. Our results show that PTC and PROP can form H-bonds with the backbone of residue 262 in the tasters (hTAS2R38PAV, hTAS2R38AAI, and hTAS2R38PVV) but not in the nontaster (hTAS2R38AVI). Thus it appears that the hydrogen bond interaction between TM3 and TM6 may activate the receptor to pass the ligand binding signal to intracellular processes and that the H-bond between agonists and residue 262 in tasters is involved in the bitter tasting. This is in agreement with experimental observations, providing validation of the predicted ligand-protein complexes and also a potential activation mechanism for the TAS2R38 receptor.


Journal of Structural Biology | 2010

Predicted 3D structures for adenosine receptors bound to ligands: comparison to the crystal structure.

William A. Goddard; Soo-Kyung Kim; Youyong Li; Bartosz Trzaskowski; Adam R. Griffith; Ravinder Abrol

G protein-coupled receptors (GPCRs) are therapeutic targets for many diseases, but progress in developing active and selective therapeutics has been severely hampered by the difficulty in obtaining accurate structures. We have been developing methods for predicting the structures for GPCR ligand complexes, but validation has been hampered by a lack of experimental structures with which to compare our predictions. We report here the predicted structures of the human adenosine GPCR subtypes (A(1), A(2A), A(2B), and A(3)) and the binding sites for adenosine agonist and eight antagonists to this predicted structure, making no use of structural data, and compare with recent experimental crystal structure for ZM241385 bound human A(2A) receptor. The predicted structure correctly identifies 9 of the 12 crystal binding site residues. Moreover, the predicted binding energies of eight antagonists to the predicted structure of A(2A) correlate quite well with experiment. These excellent predictions resulted when we used Monte Carlo techniques to optimize the loop structures, particularly the cysteine linkages. Ignoring these linkages led to a much worse predicted binding site (identifying only 3 of the 12 important residues). These results indicate that computational methods can predict the three-dimensional structure of GPCR membrane proteins sufficiently accurately for use in designing subtype selective ligands for important GPCR therapeutics targets.


Journal of Biological Inorganic Chemistry | 2007

A theoretical study of zinc(II) interactions with amino acid models and peptide fragments

Bartosz Trzaskowski; Ludwik Adamowicz; P. A. Deymier

Density functional theory calculations have been employed to study the interaction between the Zn2+ ion and some standard amino acid models. The highest affinities towards the Zn2+ ion are predicted for serine, cysteine, and histidine. Relatively high affinities are reported also for proline and glutamate/aspartate residues. It was found that the zinc complexes with cysteine adopt a tetrahedral conformation. Conversely, complexes with one or two histidine moieties remain in an octahedral geometry, while those with three or more histidine groups adopt a square-planar geometry.


PLOS ONE | 2012

The Role of Water in Activation Mechanism of Human N-Formyl Peptide Receptor 1 (FPR1) Based on Molecular Dynamics Simulations

Shuguang Yuan; Umesh Ghoshdastider; Bartosz Trzaskowski; Dorota Latek; Aleksander Debinski; Wojciech Puławski; Rongliang Wu; Volker Gerke; Slawomir Filipek

The Formyl Peptide Receptor 1 (FPR1) is an important chemotaxis receptor involved in various aspects of host defense and inflammatory processes. We constructed a model of FPR1 using as a novel template the chemokine receptor CXCR4 from the same branch of the phylogenetic tree of G-protein-coupled receptors. The previously employed template of rhodopsin contained a bulge at the extracellular part of TM2 which directly influenced binding of ligands. We also conducted molecular dynamics (MD) simulations of FPR1 in the apo form as well as in a form complexed with the agonist fMLF and the antagonist tBocMLF in the model membrane. During all MD simulation of the fMLF-FPR1 complex a water molecule transiently bridged the hydrogen bond between W2546.48 and N1083.35 in the middle of the receptor. We also observed a change in the cytoplasmic part of FPR1 of a rotamer of the Y3017.53 residue (tyrosine rotamer switch). This effect facilitated movement of more water molecules toward the receptor center. Such rotamer of Y3017.53 was not observed in any crystal structures of GPCRs which can suggest that this state is temporarily formed to pass the water molecules during the activation process. The presence of a distance between agonist and residues R2015.38 and R2055.42 on helix TM5 may suggest that the activation of FPR1 is similar to the activation of β-adrenergic receptors since their agonists are separated from serine residues on helix TM5. The removal of water molecules bridging these interactions in FPR1 can result in shrinking of the binding site during activation similarly to the shrinking observed in β-ARs. The number of GPCR crystal structures with agonists is still scarce so the designing of new ligands with agonistic properties is hampered, therefore homology modeling and docking can provide suitable models. Additionally, the MD simulations can be beneficial to outline the mechanisms of receptor activation and the agonist/antagonist sensing.


Proceedings of the National Academy of Sciences of the United States of America | 2014

Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor

Ravinder Abrol; Bartosz Trzaskowski; William A. Goddard; Alexandre Nesterov; Ivan Olave; Christopher Irons

Significance The C-C chemokine receptor type 5 (CCR5) G protein-coupled receptor (GPCR) is a prime target for preventing HIV invasion. A major difficulty in developing effective therapeutics is that the CCR5 exhibits an ensemble of ∼10–20 distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. X-ray structures generally provide only one of these conformations. We applied the GEnSeMBLE methodology to predict this ensemble, and we designed and carried out 11 experiments to validate the ability of this ensemble to predict binding of an HIV therapeutic to CCR5. We found that each of the mutations changes the binding site. The predicted effects of mutations on binding are in excellent agreement with experiments, providing CCR5 structures for designing new ligands. We predicted the structural basis for pleiotropic signaling of the C-C chemokine type 5 (CCR5) G protein-coupled receptor (GPCR) by predicting the binding of several ligands to the lower-energy conformations of the CCR5 receptor and 11 mutants. For each case, we predicted the ∼20 most stable conformations for the receptor along with the binding sites for four anti-HIV ligands. We found that none of the ligands bind to the lowest-energy apo-receptor conformation. The three ligands with a similar pharmacophore (Maraviroc, PF-232798, and Aplaviroc) bind to a specific higher-energy receptor conformation whereas TAK-779 (with a different pharmacophore) binds to a different high-energy conformation. This result is in agreement with the very different binding-site profiles for these ligands obtained by us and others. The predicted Maraviroc binding site agrees with the recent structure of CCR5 receptor cocrystallized with Maraviroc. We performed 11 site-directed mutagenesis experiments to validate the predicted binding sites. Here, we independently predicted the lowest 10 mutant protein conformations for each of the 11 mutants and then docked the ligands to these lowest conformations. We found the predicted binding energies to be in excellent agreement with our mutagenesis experiments. These results show that, for GPCRs, each ligand can stabilize a different protein conformation, complicating the use of cocrystallized structures for ligand screening. Moreover, these results show that a single-point mutation in a GPCR can dramatically alter the available low-energy conformations, which in turn alters the binding site, potentially altering downstream signaling events. These studies validate the conformational selection paradigm for the pleiotropic function and structural plasticity of GPCRs.


PLOS Computational Biology | 2013

Lipid Receptor S1P1 Activation Scheme Concluded from Microsecond All-Atom Molecular Dynamics Simulations

Shuguang Yuan; Rongliang Wu; Dorota Latek; Bartosz Trzaskowski; Slawomir Filipek

Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator which activates G protein–coupled sphingosine 1-phosphate receptors and thus evokes a variety of cell and tissue responses including lymphocyte trafficking, endothelial development, integrity, and maturation. We performed five all-atom 700 ns molecular dynamics simulations of the sphingosine 1-phosphate receptor 1 (S1P1) based on recently released crystal structure of that receptor with an antagonist. We found that the initial movements of amino acid residues occurred in the area of highly conserved W2696.48 in TM6 which is close to the ligand binding location. Those residues located in the central part of the receptor and adjacent to kinks of TM helices comprise of a transmission switch. Side chains movements of those residues were coupled to the movements of water molecules inside the receptor which helped in the gradual opening of intracellular part of the receptor. The most stable parts of the protein were helices TM1 and TM2, while the largest movement was observed for TM7, possibly due to the short intracellular part starting with a helix kink at P7.50, which might be the first helix to move at the intracellular side. We show for the first time the detailed view of the concerted action of the transmission switch and Trp (W6.48) rotamer toggle switch leading to redirection of water molecules flow in the central part of the receptor. That event is a prerequisite for subsequent changes in intracellular part of the receptor involving water influx and opening of the receptor structure.


Journal of Virology | 2013

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Reem Berro; Anila Yasmeen; Ravinder Abrol; Bartosz Trzaskowski; Sarya Abi-Habib; Amy Grunbeck; Danny Lascano; William A. Goddard; Per Johan Klasse; Thomas P. Sakmar; John P. Moore

ABSTRACT Small-molecule CCR5 inhibitors such as vicriviroc (VVC) and maraviroc (MVC) are allosteric modulators that impair HIV-1 entry by stabilizing a CCR5 conformation that the virus recognizes inefficiently. Viruses resistant to these compounds are able to bind the inhibitor-CCR5 complex while also interacting with the free coreceptor. CCR5 also interacts intracellularly with G proteins, as part of its signal transduction functions, and this process alters its conformation. Here we investigated whether the action of VVC against inhibitor-sensitive and -resistant viruses is affected by whether or not CCR5 is coupled to G proteins such as Gαi. Treating CD4+ T cells with pertussis toxin to uncouple the Gαi subunit from CCR5 increased the potency of VVC against the sensitive viruses and revealed that VVC-resistant viruses use the inhibitor-bound form of Gαi-coupled CCR5 more efficiently than they use uncoupled CCR5. Supportive evidence was obtained by expressing a signaling-deficient CCR5 mutant with an impaired ability to bind to G proteins, as well as two constitutively active mutants that activate G proteins in the absence of external stimuli. The implication of these various studies is that the association of intracellular domains of CCR5 with the signaling machinery affects the conformation of the external and transmembrane domains and how they interact with small-molecule inhibitors of HIV-1 entry.

Collaboration


Dive into the Bartosz Trzaskowski's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar

Abraham F. Jalbout

National Autonomous University of Mexico

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

William A. Goddard

California Institute of Technology

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Ravinder Abrol

California Institute of Technology

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge