Papers by Ahmad Reza Mehdipour
Nature Communications
Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We re... more Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the var...
Iranian Journal of Pharmaceutical Research, 2009
Dihydropyridine calcium channel blockers consist one of the widely-used groups of drugs for the m... more Dihydropyridine calcium channel blockers consist one of the widely-used groups of drugs for the management of hypertension. In this study, antihypertensive effects of 5 newly synthesized derivatives of DHP was examined the in rat model of two-kidney, one-clip renal hypertension. The results showed that those compounds containing two nitroxy groups had less decreasing effect on MAP (Men Arterial Pressure) compared to those having one nitroxy group in 5 position. On the other hand, conformational analysis indicated that in two compounds with two chains (A and E), a great steric hindrance existed; therefore, steric hindrance is the most important factor for interaction of compounds with their receptors.
Proceedings of the National Academy of Sciences, 2021
Significance Multidrug and toxic compound extrusion (MATE) transporters play a significant role i... more Significance Multidrug and toxic compound extrusion (MATE) transporters play a significant role in the active export of drugs and toxic compounds in pathogens. The transport mechanism is still not fully understood. A comprehensive phylogenetic analysis indicates that Aq_128 of Aquifex aeolicus is a member of a subfamily of MATE transporters together with transporters from ε-Proteobacteria and Archaea. The high-resolution crystal structure (2.0 Å) in combination with drug efflux assays, mutagenesis studies, docking experiments, and molecular dynamics simulations reveals structural features that differ from previously described MATE transporters, and sheds light on their transport mechanism.
Nature, 2020
The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing... more The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread 1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses 3-5. Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity. The novel coronavirus SARS-CoV-2 is the cause of the current worldwide outbreak of the respiratory disease coronavirus disease 2019 (COVID-19) 6. COVID-19 generally has less severe symptoms and a lower case-fatality rate but is transmitted more rapidly compared with the related SARS-CoV, which caused the SARS outbreak in 2003. The SARS-CoV-2 genome shares high sequence identity with SARS-CoV 7,8. Both viruses critically rely on the activity of viral proteases: the main protease (Mpro, also known as 3CLpro or non-structural protein 5 (nsp5)) and the papain-like protease (PLpro, the protease domain of nsp3) to generate a functional replicase complex and enable viral spread 1,2. SCoV-PLpro cleaves ubiquitin and ISG15, known regulators of host innate immune pathways, and inhibition of SCoV-PLpro has been shown to block SARS-CoV replication 3-5. SARS-CoV-2 PLpro preferentially cleaves ISG15 SCoV-PLpro and SCoV2-PLpro are closely related and diverge from Middle East respiratory syndrome (MERS) coronavirus PLpro (MERS-PLpro) (Extended Data Fig. 1a). Purified SCoV-PLpro and SCoV2-PLpro exhibit differences in their substrate preferences, as revealed by their cleavage of ubiquitin or ISG15 from substrates in HeLa cells treated with interferon-α (IFN-α) (Extended Data Fig. 1b). SCoV-PLpro strongly reduced the appearance of ubiquitinated substrates, with a lesser effect on ISGylated substrates, whereas SCoV2-PLpro preferentially reduced appearance of ISG15-conjugated (ISGylated) protein substrates (Extended Data Fig. 1b). We next used activity-based probes, namely a highly reactive propargylamide (Prg) 'warhead', which forms a covalent bond with
eLife, 2020
Legionella pneumophila causes a severe pneumonia known as Legionnaires’ disease. During the infec... more Legionella pneumophila causes a severe pneumonia known as Legionnaires’ disease. During the infection, Legionella injects more than 300 effector proteins into host cells. Among them are enzymes involved in altering the host-ubiquitination system. Here, we identified two LegionellaOTU (ovarian tumor)-like deubiquitinases (LOT-DUBs; LotB [Lpg1621/Ceg23] and LotC [Lpg2529]). The crystal structure of the LotC catalytic core (LotC14-310) was determined at 2.4 Å. Unlike the classical OTU-family, the LOT-family shows an extended helical lobe between the Cys-loop and the variable loop, which defines them as a unique class of OTU-DUBs. LotB has an additional ubiquitin-binding site (S1’), which enables the specific cleavage of Lys63-linked polyubiquitin chains. By contrast, LotC only contains the S1 site and cleaves different species of ubiquitin chains. MS analysis of LotB and LotC identified different categories of host-interacting proteins and substrates. Together, our results provide new ...
Legionella pneumophila is a gram-negative pathogenic bacterium that causes Legionaries’ disease. ... more Legionella pneumophila is a gram-negative pathogenic bacterium that causes Legionaries’ disease. The Legionella genome codes more than 300 effector proteins able to modulate host-pathogen interactions during infection. Among them are also enzymes altering the host-ubiquitination system including bacterial ligases and deubiquitinases. In this study, based on homology-detection screening on 305 Legionella effector proteins, we identified two LegionellaOTU-like deubiquitinases (LOT; LotB (Lpg1621/Ceg23) and LotC (Lpg2529), LotA (Lpg2248/Lem21) is already known). A crystal structure of LotC catalytic core (LotC14-310) was determined at 2.4 Å and compared with other OTU deubiquitinases, including LotB. Unlike the classical OTU-family, the structures of Legionella OTU-family (LotB and LotC) shows an extended helical lobe between the Cys-loop and the variable loop, which define a novel class of OTU-deubiquitinase. Despite structural differences in their helical lobes, both LotB and LotC in...
Structure, 2019
Highlights d An outward semi-occluded structure of PglK with ATPgSbound is shown d Molecular dyna... more Highlights d An outward semi-occluded structure of PglK with ATPgSbound is shown d Molecular dynamics simulations show a recognition site for LLO d Sugars from the LLO head group are essential for translocation d LLO release is a pre-hydrolysis event followed by quick closure of the cavity
Nature communications, Jan 31, 2018
The membrane-associated, processive and retaining glycosyltransferase PglH from Campylobacter jej... more The membrane-associated, processive and retaining glycosyltransferase PglH from Campylobacter jejuni is part of the biosynthetic pathway of the lipid-linked oligosaccharide (LLO) that serves as the glycan donor in bacterial protein N-glycosylation. Using an unknown counting mechanism, PglH catalyzes the transfer of exactly three α1,4 N-acetylgalactosamine (GalNAc) units to the growing LLO precursor, GalNAc-α1,4-GalNAc-α1,3-Bac-α1-PP-undecaprenyl. Here, we present crystal structures of PglH in three distinct states, including a binary complex with UDP-GalNAc and two ternary complexes containing a chemo-enzymatically generated LLO analog and either UDP or synthetic, nonhydrolyzable UDP-CH-GalNAc. PglH contains an amphipathic helix ("ruler helix") that has a dual role of facilitating membrane attachment and glycan counting. The ruler helix contains three positively charged side chains that can bind the pyrophosphate group of the LLO substrate and thus limit the addition of Ga...
eLife, Jan 16, 2017
Ion channel gating is essential for cellular homeostasis and is tightly controlled. In some eukar... more Ion channel gating is essential for cellular homeostasis and is tightly controlled. In some eukaryotic and most bacterial ligand-gated K(+) channels, RCK domains regulate ion fluxes. Until now, a single regulatory mechanism has been proposed for all RCK-regulated channels, involving signal transduction from the RCK domain to the gating area. Here, we present an inactive ADP-bound structure of KtrAB from Vibrio alginolyticus, determined by cryo-electron microscopy, which, combined with EPR spectroscopy and molecular dynamics simulations, uncovers a novel regulatory mechanism for ligand-induced action at a distance. Exchange of activating ATP to inactivating ADP triggers short helical segments in the K(+)-translocating KtrB dimer to organize into two long helices that penetrate deeply into the regulatory RCK domains, thus connecting nucleotide-binding sites and ion gates. As KtrAB and its homolog TrkAH have been implicated as bacterial pathogenicity factors, the discovery of this func...
Proceedings of the National Academy of Sciences of the United States of America, Jan 24, 2017
ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing... more ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing the movement of diverse substrates across membranes. In this key position, ABC transporters can mediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-Å X-ray structure of heterodimeric Thermus thermophilus multidrug resistance proteins A and B (TmrAB), which not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. In our structure, TmrAB adopts an asymmetric inward-facing state, and we show that the C-terminal helices, arranged in a zipper-like fashion, play a crucial role in guiding the conformational changes associated with substrate transport. In conclusion, TmrAB can be reg...
Proceedings of the National Academy of Sciences of the United States of America, Jan 2, 2016
Biophysical Journal, 2014
Biochemistry, 2014
Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is require... more Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is required for termination of synaptic transmission. Transport is tightly regulated by protein−protein interactions involving the small cytoplasmic segments at the amino-and carboxy-terminal ends of the transporter. Although structures of homologues provide information about the transmembrane regions of these transporters, the structural arrangement of the terminal domains remains largely unknown. Here, we combined molecular modeling, biochemical, and biophysical approaches in an iterative manner to investigate the structure of the 82-residue N-terminal and 30-residue C-terminal domains of human serotonin transporter (SERT). Several secondary structures were predicted in these domains, and structural models were built using the Rosetta fragment-based methodology. One-dimensional 1 H nuclear magnetic resonance and circular dichroism spectroscopy supported the presence of helical elements in the isolated SERT N-terminal domain. Moreover, introducing helix-breaking residues within those elements altered the fluorescence resonance energy transfer signal between terminal cyan fluorescent protein and yellow fluorescent protein tags attached to full-length SERT, consistent with the notion that the fold of the terminal domains is relatively well-defined. Full-length models of SERT that are consistent with these and published experimental data were generated. The resultant models predict confined loci for the terminal domains and predict that they move apart during the transport-related conformational cycle, as predicted by structures of homologues and by the "rocking bundle" hypothesis, which is consistent with spectroscopic measurements. The models also suggest the nature of binding to regulatory interaction partners. This study provides a structural context for functional and regulatory mechanisms involving SERT terminal domains.
Nature Communications, 2014
The Na þ-coupled betaine symporter BetP shares a highly conserved fold with other sequence unrela... more The Na þ-coupled betaine symporter BetP shares a highly conserved fold with other sequence unrelated secondary transporters, for example, with neurotransmitter symporters. Recently, we obtained atomic structures of BetP in distinct conformational states, which elucidated parts of its alternating-access mechanism. Here, we report a structure of BetP in a new outward-open state in complex with an anomalous scattering substrate, adding a fundamental piece to an unprecedented set of structural snapshots for a secondary transporter. In combination with molecular dynamics simulations these structural data highlight important features of the sequential formation of the substrate and sodium-binding sites, in which coordinating water molecules play a crucial role. We observe a strictly interdependent binding of betaine and sodium ions during the coupling process. All three sites undergo progressive reshaping and dehydration during the alternating-access cycle, with the most optimal coordination of all substrates found in the closed state.
Medicinal Chemistry Research, 2010
4-Hydroxycoumarins constitute the structural nucleus of many natural products, drugs, and pestici... more 4-Hydroxycoumarins constitute the structural nucleus of many natural products, drugs, and pesticides. Promising biological properties in new families of synthetic coumarins were recently reported. Therefore, efficient synthesis of new benzopyrano[3,2-c]chromene-6,8-dione was undertaken and the structures of 15 compounds were confirmed by their IR, Mass, 1H-NMR, and C, H, N analysis. Then, the cytotoxic activities of these compounds were assessed on
Journal of the Iranian Chemical Society, 2012
The autocorrelation analysis of the quantum topological molecular similarity (QTMS) has been used... more The autocorrelation analysis of the quantum topological molecular similarity (QTMS) has been used to discover some new indices for amino acids. QTMS descriptors include both physical and topological property molecules and produce a matrix of variables per molecule. To handle cubic array of QTMS descriptor calculated for a list of 20 naturally occurring amino acids, autocorrelation analysis has been performed. The proposed indices were validated by construction of quantitative sequence-activity model for three sets of peptides with different chain sizes. Modeling procedure used genetic algorithm-partial least square as variable selection and regression tools. The obtained models were of better or similar qualities compared with previously reported models for the same data sets. Also, the proposed indices in this article were able to determine active site region of the peptides under study.
Journal of Computational Chemistry, 2009
When using quantum chemical descriptors in quantitative structure-activity relationship (QSAR) st... more When using quantum chemical descriptors in quantitative structure-activity relationship (QSAR) studies, there is always a challenge between accuracy of calculation and the complexity and time of computation. Very recently, we proposed the use of substituents electronic descriptors (SEDs) instead of the electronic properties of whole molecule as new and expedite source of electronic descriptors. For instance, SED parameters can be calculated with the highest degree of accuracy in very low computation time. In this article, we used SED parameters in QSAR modeling of six different biological data sets including (i) the dissociation constants for a set of substituted imidazolines, (ii) the pKa of imidazoles, (iii) inverse agonist activity of indoles, (iv) the influenza virus inhibition activities of benzimidazoles, (v) inhibition of alcohol dehydrogenase by amides, and (vi) the natriuretic activity of sulfonamide. For poly-substituted molecules, SED parameters produce a vector of electronic descriptors for each substituent, and thus a matrix of SED parameters is obtained for each molecule. Consequently, a three-dimensional (3D) array is obtained by staking the descriptor data matrices of molecules beside each others. In addition to simple unfolding of the SED parameters, molecular maps of atom-level properties (MOLMAP) approach, as a novel data analysis method, was also applied to transfer 3D array of SED into new two-dimensional parameters using Kohonen network, following by genetic algorithm-based partial least square (GA-PLS) to connect a quantitative relationship between the Kohonen scores and biological activity. Accurate QSAR models were obtained by both approaches. However, the superiority of three-way analysis of SED parameters based on MOLMAP approach with respect to simple unfolding was obtained.
Drug Discovery Today, 2009
The treatment of brain disorders is limited by the insufficiency in delivering therapeutic drugs ... more The treatment of brain disorders is limited by the insufficiency in delivering therapeutic drugs into brain relating to highly limited transport of compounds through blood-brain barrier (BBB). Therefore, a lot of attempts have been made to rise above this problem using a variety of approaches. In this way, in silico techniques try to predict the brain permeability based on a range of physicochemical descriptors resulting from structures of the corresponding compounds. Most of the models have some disadvantages, which preclude making conclusive decision. The major defect is ignoring the main parts of process of permeability using only total concentrations for modeling. Moreover, the role of transporters is underestimated in addition to neglecting the complex nature of BBB, which, collectively, leads to uncertain results. Reviews INFORMATICS
Clinical Therapeutics, 2010
Background: Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and ... more Background: Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and treatment of venous and arterial thromboembolic disorders. Its anticoagulant effect is widely variable between patients because of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors. Objective: This study was conducted to identify the associations between demographic characteristics, warfarin maintenance dose, and genetic polymorphisms of cytochrome P450 (CYP) 2C19, CYP2C9, and vitamin K epoxide reductase complex subunit 1 (VKORC1). Methods: This study was conducted from April 2005 to April 2008 at 3 warfarin clinics affiliated with Shiraz University of Medical Sciences. Blood samples were collected from patients with stable warfarin maintenance dose and a stable target international normalized ratio of 2 to 3. Patients who had a condition (including use of an interacting medication) affecting the metabolism of warfarin were excluded. CYP2C9, CYP2C19, and VKORC1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. The associations between demographic characteristics (eg, age, sex, body surface area, weight, height), genetic factors, and maintenance warfarin dose were examined by multiple linear regression. The probability of F as a criterion for removal of a variable from the multiple linear regression was set at 0.1. Results: One hundred patients were enrolled in the study; complete data were available for 55, who were included in the regression analysis. Among this smaller group, the mean (SD) age was 53 (11) years (range, 25-80 years) and mean weight was 72 (15) kg (range, 42-125 kg); the mean warfarin dose was 27.2 (13.4) mg/week. The allelic frequencies of CYP2C9*2 and CYP2C9*3 were 27% and 9%, respectively. The allelic frequencies of CYP2C19*2 and CYP2C19*3 were 11% and 1%, respectively. Fifteen percent of our patients carried a VKORC1 genotype GG, whereas the AA and GA genotypes were seen in 18% and 58% of patients, respectively. Multiple linear regression analysis found that sex (P = 0.045), height (P = 0.024), age (P = 0.081), and VKORC1 (P = 0.004) and CYP2C9 (P = 0.011) polymorphism had significant influence on the maintenance dose of warfarin. They were associated with 41.3% of the variability in warfarin maintenance dose requirement. VKORC1 polymorphism (partial R 2 = 20.3%) and height (partial R 2 = 20.3%) had the greatest effects on warfarin maintenance dose requirement. Conclusion: Among the demographic and genetic factors evaluated in these Iranian patients, sex, height, age, CYP2C9, and VKORC1 had significant effects on warfarin maintenance dose requirements.
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Chemical Biology & Drug Design, 2011
Thirty novel derivatives of aza‐cyclopenta[b]fluorene‐1,9‐dione were synthesized, and their cytot... more Thirty novel derivatives of aza‐cyclopenta[b]fluorene‐1,9‐dione were synthesized, and their cytotoxic activities were tested against HeLa, LS180, MCF‐7, and Raji cancer cell lines by MTT assay. Two derivatives containing nitrofuryl moiety, including 10‐(5‐nitro‐furan‐2‐yl)‐2,3‐dihydro‐4‐aza‐cyclopenta[b]fluorene‐1,9‐dione (IC50 range: 5.7–13.0 μm) and 10‐(5‐Nitro‐furan‐2‐yl)‐2,3,4,10‐tetrahydro‐4‐aza‐cyclopenta[b]fluorene‐1,9‐dione (IC50 range: 3.6–20.2 μm), as well as 10‐(2‐Nitro‐phenyl)‐2,3,4,10‐tetrahydro‐4‐aza‐cyclopenta[b]fluorene‐1,9‐dione (IC50 range: 3.1–27.1 μm) with nitrophenyl moiety on C10 position, were the most effective compounds. Furthermore, the effect of physiochemical descriptors on the cytotoxicity was evaluated by quantitative structure–activity relationship analysis. The quantitative structure–activity relationship results showed that molecular dipole moment, molar refractivity, fragment‐based parameters, and some topological indices were influential on the cyt...
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Papers by Ahmad Reza Mehdipour