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Dive into the research topics where Henry I. Mosberg is active.

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Featured researches published by Henry I. Mosberg.


Bioinformatics | 2006

OPM: Orientations of Proteins in Membranes database

Mikhail A. Lomize; Irina D. Pogozheva; Henry I. Mosberg

SUMMARY The Orientations of Proteins in Membranes (OPM) database provides a collection of transmembrane, monotopic and peripheral proteins from the Protein Data Bank whose spatial arrangements in the lipid bilayer have been calculated theoretically and compared with experimental data. The database allows analysis, sorting and searching of membrane proteins based on their structural classification, species, destination membrane, numbers of transmembrane segments and subunits, numbers of secondary structures and the calculated hydrophobic thickness or tilt angle with respect to the bilayer normal. All coordinate files with the calculated membrane boundaries are available for downloading. AVAILABILITY http://opm.phar.umich.edu.


Nucleic Acids Research | 2012

OPM database and PPM web server: resources for positioning of proteins in membranes

Mikhail A. Lomize; Irina D. Pogozheva; Hyeon Joo; Henry I. Mosberg

The Orientations of Proteins in Membranes (OPM) database is a curated web resource that provides spatial positions of membrane-bound peptides and proteins of known three-dimensional structure in the lipid bilayer, together with their structural classification, topology and intracellular localization. OPM currently contains more than 1200 transmembrane and peripheral proteins and peptides from approximately 350 organisms that represent approximately 3800 Protein Data Bank entries. Proteins are classified into classes, superfamilies and families and assigned to 21 distinct membrane types. Spatial positions of proteins with respect to the lipid bilayer are optimized by the PPM 2.0 method that accounts for the hydrophobic, hydrogen bonding and electrostatic interactions of the proteins with the anisotropic water-lipid environment described by the dielectric constant and hydrogen-bonding profiles. The OPM database is freely accessible at http://opm.phar.umich.edu. Data can be sorted, searched or retrieved using the hierarchical classification, source organism, localization in different types of membranes. The database offers downloadable coordinates of proteins and peptides with membrane boundaries. A gallery of protein images and several visualization tools are provided. The database is supplemented by the PPM server (http://opm.phar.umich.edu/server.php) which can be used for calculating spatial positions in membranes of newly determined proteins structures or theoretical models.


Biophysical Journal | 2002

Membrane Composition Determines Pardaxin's Mechanism of Lipid Bilayer Disruption

Kevin Hallock; Dong Kuk Lee; John R. Omnaas; Henry I. Mosberg; Ayyalusamy Ramamoorthy

Pardaxin is a membrane-lysing peptide originally isolated from the fish Pardachirus marmoratus. The effect of the carboxy-amide of pardaxin (P1a) on bilayers of varying composition was studied using (15)N and (31)P solid-state NMR of mechanically aligned samples and differential scanning calorimetry (DSC). (15)N NMR spectroscopy of [(15)N-Leu(19)]P1a found that the orientation of the peptides C-terminal helix depends on membrane composition. It is located on the surface of lipid bilayers composed of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and is inserted in lipid bilayers composed of 1,2-dimyristoyl-phosphatidylcholine (DMPC). The former suggests a carpet mechanism for bilayer disruption whereas the latter is consistent with a barrel-stave mechanism. The (31)P chemical shift NMR spectra showed that the peptide significantly disrupts lipid bilayers composed solely of zwitterionic lipids, particularly bilayers composed of POPC, in agreement with a carpet mechanism. P1a caused the formation of an isotropic phase in 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE) lipid bilayers. This, combined with DSC data that found P1a reduced the fluid lamellar-to-inverted hexagonal phase transition temperature at very low concentrations (1:50,000), is interpreted as the formation of a cubic phase and not micellization of the membrane. Experiments exploring the effect of P1a on lipid bilayers composed of 4:1 POPC:cholesterol, 4:1 POPE:cholesterol, 3:1 POPC:1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), and 3:1 POPE:POPG were also conducted, and the presence of anionic lipids or cholesterol was found to reduce the peptides ability to disrupt bilayers. Considered together, these data demonstrate that the mechanism of P1a is dependent on membrane composition.


Protein Science | 2006

Positioning of proteins in membranes: A computational approach

Irina D. Pogozheva; Mikhail A. Lomize; Henry I. Mosberg

A new computational approach has been developed to determine the spatial arrangement of proteins in membranes by minimizing their transfer energies from water to the lipid bilayer. The membrane hydrocarbon core was approximated as a planar slab of adjustable thickness with decadiene‐like interior and interfacial polarity profiles derived from published EPR studies. Applicability and accuracy of the method was verified for a set of 24 transmembrane proteins whose orientations in membranes have been studied by spin‐labeling, chemical modification, fluorescence, ATR FTIR, NMR, cryo‐microscopy, and neutron diffraction. Subsequently, the optimal rotational and translational positions were calculated for 109 transmembrane, five integral monotopic and 27 peripheral protein complexes with known 3D structures. This method can reliably distinguish transmembrane and integral monotopic proteins from water‐soluble proteins based on their transfer energies and membrane penetration depths. The accuracies of calculated hydrophobic thicknesses and tilt angles were ∼1 Å and 2°, respectively, judging from their deviations in different crystal forms of the same proteins. The hydrophobic thicknesses of transmembrane proteins ranged from 21.1 to 43.8 Å depending on the type of biological membrane, while their tilt angles with respect to the bilayer normal varied from zero in symmetric complexes to 26° in asymmetric structures. Calculated hydrophobic boundaries of proteins are located ∼5 Å lower than lipid phosphates and correspond to the zero membrane depth parameter of spin‐labeled residues. Coordinates of all studied proteins with their membrane boundaries can be found in the Orientations of Proteins in Membranes (OPM) database:http://opm.phar.umich.edu/.


Journal of Biological Chemistry | 2009

Purification and Functional Reconstitution of Monomeric μ-Opioid Receptors ALLOSTERIC MODULATION OF AGONIST BINDING BY Gi2

Adam J. Kuszak; Sethuramasundaram Pitchiaya; Jessica P. Anand; Henry I. Mosberg; Nils G. Walter; Roger K. Sunahara

Despite extensive characterization of the μ-opioid receptor (MOR), the biochemical properties of the isolated receptor remain unclear. In light of recent reports, we proposed that the monomeric form of MOR can activate G proteins and be subject to allosteric regulation. A μ-opioid receptor fused to yellow fluorescent protein (YMOR) was constructed and expressed in insect cells. YMOR binds ligands with high affinity, displays agonist-stimulated [35S]guanosine 5′-(γ-thio)triphosphate binding to Gαi, and is allosterically regulated by coupled Gi protein heterotrimer both in insect cell membranes and as purified protein reconstituted into a phospholipid bilayer in the form of high density lipoprotein particles. Single-particle imaging of fluorescently labeled receptor indicates that the reconstituted YMOR is monomeric. Moreover, single-molecule imaging of a Cy3-labeled agonist, [Lys7, Cys8]dermorphin, illustrates a novel method for studying G protein-coupled receptor-ligand binding and suggests that one molecule of agonist binds per monomeric YMOR. Together these data support the notion that oligomerization of the μ-opioid receptor is not required for agonist and antagonist binding and that the monomeric receptor is the minimal functional unit in regard to G protein activation and strong allosteric regulation of agonist binding by G proteins.


Brain Research | 1987

Opioid δ-receptor involvement in supraspinal and spinal antinociception in mice

Julius S. Heyman; Sheila A. Mulvaney; Henry I. Mosberg; Frank Porreca

The possibility that the opioid r morphine) and b ([D-Pen2,D-PenS]enkephalin, DPDPE)-agonists in the absence, and in the presence of the/~ non-surmountable antagonist, fl-funaltrexamine (fl-FNA) or the b-antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-LeuOH, where Aib is a-amino-isobutyric acid), Agonists and 1CI 174,864 were given alone or in the same intracerebroventricular (i.c.v.) or intrathecal (i.th.) injection to mice 20 min prior to testing in the warm-water (55 °C) tail-withdrawal test (+10 min for i.th. DPDPE); fl-FNA was given as a single i.c.v, or i.th. pretreatment dose (20 and 0.01 nM, respectively) 4 h prior to testing. I.c.v. pretreatment with fl-FNA resulted in a rightward displacement of the DAGO and morphine antinociceptive dose-response lines, but failed to displace the i.c.v. DPDPE curve. Similarly, i.th. pretreatment with/3-FNA displaced the i.th. morphine dose-response curve to the right without affecting the i.th. DPDPE antinociceptive dose-response line. ICI 174,864 (1 and 3 #g) produced a dose-related antagonism of i.c.v, or i.th. DPDPE, but did not alter the antinociceptive effects of DAGO or morphine given by the same routes. Co-administration of ICI 174,864 (3/~g) with i.c.v, morphine in fl-FNA pretreated (but not control) mice resulted in a further rightward displacement of the morphine dose-response line. The effective antagonism of DPDPE but not morphine or DAGO antinociception by ICI 174,864, together with the effectiveness of fl-FNA against morphine and DAGO but not DPDPE antinociception, provide strong and direct evidence for the involvement of cerebral and spinal b-receptors in the mediation of antinociception in tests where heat is employed as the noxious stimulus. Additionally, the effectiveness of ICI 174,864 against morphine in/3-FNA pretreated (but not control) mice demonstrates a b-effect of morphine, in vivo.


European Journal of Pharmacology | 1989

Modulation of μ-mediated antinociception by δ agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2, D-Pen5]enkephalin

Julius S. Heyman; Jeffry L. Vaught; Henry I. Mosberg; Ronald C. Haaseth; Frank Porreca

The effect of the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) on the antinociception produced by intracerebroventricular (i.c.v.) administration of the mu agonists morphine, [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO), [NMePhe3,D-Pro4]morphiceptin (PLO17), beta-endorphin, phenazocine, etorphine and sufentanil was studied in mice. Only the antinociceptive effects of morphine and normorphine were modulated by i.c.v. coadministration of a dose of DPDPE which did not produce any significant antinociception alone. Both the morphine and normorphine dose-response lines were displaced to the left in the presence of DPDPE. The delta-selective antagonist ICI174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is alpha-aminoisobutyric acid) blocked the modulation of morphine antinociception by DPDPE. ICI 174,864 alone failed to produce either a significant increase or decrease of morphine, phenazocine, etorphine or beta-endorphin antinociception. The results of the present study provide support for the hypothesis that the enkephalins may function to modulate antinociception produced at the mu receptor; such modulation may come about via the existence of an opioid mu-delta receptor complex. The mu receptors existing in such a complex may be selectively activated by morphine and normorphine, but not the other mu agonists studied here. Thus, the enkephalins may function both to directly initiate, as well as to modulate, some forms of supraspinal mu receptor-mediated antinociception.


Journal of Neurochemistry | 2002

Key Residues Defining the μ‐Opioid Receptor Binding Pocket: A Site‐Directed Mutagenesis Study

Alfred Mansour; Larry P. Taylor; Jeffrey L. Fine; Robert C. Thompson; Mary T. Hoversten; Henry I. Mosberg; Stanley J. Watson; Huda Akil

Abstract: Structural elements of the rat μ‐opioid receptor important in ligand receptor binding and selectivity were examined using a site‐directed mutagenesis approach. Five single amino acid mutations were made, three that altered conserved residues in the μ, δ, and κ receptors (Asn150 to Ala, His297 to Ala, and Tyr326 to Phe) and two designed to test for μ/δ selectivity (Ile198 to Val and Val202 to Ile). Mutation of His297 in transmembrane domain 6 (TM6) resulted in no detectable binding with [3H]DAMGO (3H‐labeled d‐Ala2,N‐Me‐Phe4,Gly‐ol5‐enkephalin), [3H]bremazocine, or [3H]ethylketocyclazocine. Mutation of Asn150 in TM3 produces a three‐ to 20‐fold increase in affinity for the opioid agonists morphine, DAMGO, fentanyl, β‐endorphin1–31, JOM‐13, deltorphin II, dynorphin1–13, and U50,488, with no change in the binding of antagonists such as naloxone, naltrexone, naltrindole, and nor‐binaltorphamine. In contrast, the Tyr326 mutation in TM7 resulted in a decreased affinity for a wide spectrum of μ, δ, and κ agonists and antagonists. Altering Val202 to Ile in TM4 produced no change on ligand affinity, but Ile198 to Val resulted in a four‐ to fivefold decreased affinity for the μ agonists morphine and DAMGO, with no change in the binding affinities of κ and δ ligands.


Pharmaceutical Research | 1989

Use of the Peptide Carrier System to Improve the Intestinal Absorption of L-α-Methyldopa: Carrier Kinetics, Intestinal Permeabilities, and In Vitro Hydrolysis of Dipeptidyl Derivatives of L-α-Methyldopa

Ming Hu; Pullachipatti Subramanian; Henry I. Mosberg; Gordon L. Amidon

Intestinal permeabilities of five dipeptidyl derivatives of L-α-methyldopa (I) were studied by an in situ intestinal perfusion method. The dipeptides displayed a significant increase in their permeabilities compared to L-α-methyldopa. The increases ranged from 4 to 20 times. These results suggest that the peptide transport system is less structurally specific than the amino acid transport systems and can be used as an absorption pathway for peptide analogues. The kinetic advantage demonstrated by the dipeptide, L-α-methyldopa-L-phenylalanine, over the amino acid analogue, L-α-methyldopa, suggests that the peptide carrier would be a possible route for improving the intestinal absorption of pharmacologically active amino acid analogues. Furthermore, the preliminary results of in vitro hydrolysis studies of selected dipeptidyl derivatives indicate that the peptide carrier system could be used as a base for a prodrug strategy.


Life Sciences | 1983

Conformationally constrained cyclic enkephalin analogs with pronounced delta opioid receptor agonist selectivity

Henry I. Mosberg; Robin Hurst; Victor J. Hruby; James J. Galligan; Thomas F. Burks; Kelvin W. Gee; Henry I. Yamamura

The enkephalin analogs, [D-Pen2,L-Cys5]- and [D-Pen2,D-Cys5]-enkephalin are cyclic compounds, conformationally constrained by virtue of their 14-membered, disulfide containing rings and by the rigidizing effect of the beta, beta dimethyl substituents of the penicillamine side chain. The analogs exhibit profound delta receptor specificity as assessed by their relative potencies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays, exhibiting, respectively, 666 and 215 times higher potency in the latter assay system. By contrast, the receptor selectivities measured in rat brain binding assays in the absence of sodium were much more modest, the cyclic analogs being, respectively, 15.2 and 6.0 times more effective at displacing [3H] [D-Ala2,D-Leu5]enkephalin than [3H]naloxone. However, for binding assays performed in the presence of a sodium concentration equivalent to that used in the GPI and MVD assays, these binding selectivities increased to 167 and 49, respectively.

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