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Dive into the research topics where Günther H. Peters is active.

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Featured researches published by Günther H. Peters.


Journal of Biological Chemistry | 2009

Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 Receptor

Christina Rye Underwood; Patrick William Garibay; Lotte Bjerre Knudsen; Sven Hastrup; Günther H. Peters; Rainer Rudolph; Steffen Reedtz-Runge

GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic β-cells in a glucose-dependent manner. The GLP-1 receptor belongs to class B of the G-protein-coupled receptors, a subfamily characterized by a large N-terminal extracellular ligand binding domain. Exendin-4 and GLP-1 are 50% identical, and exendin-4 is a full agonist with similar affinity and potency for the GLP-1 receptor. We recently solved the crystal structure of the GLP-1 receptor extracellular domain in complex with the competitive antagonist exendin-4(9–39). Interestingly, the isolated extracellular domain binds exendin-4 with much higher affinity than the endogenous agonist GLP-1. Here, we have solved the crystal structure of the extracellular domain in complex with GLP-1 to 2.1 Åresolution. The structure shows that important hydrophobic ligand-receptor interactions are conserved in agonist- and antagonist-bound forms of the extracellular domain, but certain residues in the ligand-binding site adopt a GLP-1-specific conformation. GLP-1 is a kinked but continuous α-helix from Thr13 to Val33 when bound to the extracellular domain. We supplemented the crystal structure with site-directed mutagenesis to link the structural information of the isolated extracellular domain with the binding properties of the full-length receptor. The data support the existence of differences in the binding modes of GLP-1 and exendin-4 on the full-length GLP-1 receptor.


Molecular and Cellular Biology | 2001

Structural and Evolutionary Relationships among Protein Tyrosine Phosphatase Domains

Jannik N. Andersen; Ole Hartvig Mortensen; Günther H. Peters; Paul G. Drake; Lars Fogh Iversen; Ole Hvilsted Olsen; Peter Gildsig Jansen; Henrik Sune Andersen; Nicholas K. Tonks; Niels Møller

With the current access to the whole genomes of various organisms and the completion of the first draft of the human genome, there is a strong need for a structure-function classification of protein families as an initial step in moving from DNA databases to a comprehensive understanding of human biology. As a result of the explosion in nucleic acid sequence information and the concurrent development of methods for high-throughput functional characterization of gene products, the genomic revolution also promises to provide a new paradigm for drug discovery, enabling the identification of molecular drug targets in a significant number of human diseases. This molecular view of diseases has contributed to the importance of combining primary sequence data with three-dimensional structure and has increased the awareness of computational homology modeling and its potential to elucidate protein function. In particular, when important proteins or novel therapeutic targets are identified—like the family of protein tyrosine phosphatases (PTPs) (reviewed in reference 53)—a structure-function classification of such protein families becomes an invaluable framework for further advances in biomedical science. Here, we present a comparative analysis of the structural relationships among vertebrate PTP domains and provide a comprehensive resource for sequence analysis of phosphotyrosine-specific PTPs.


Journal of Chemical Physics | 2005

Methodological problems in pressure profile calculations for lipid bilayers

Jacob Sonne; Flemming Y. Hansen; Günther H. Peters

From molecular dynamics simulations of a dipalmitoyl-phosphatidyl-choline (DPPC) lipid bilayer in the liquid crystalline phase, pressure profiles through the bilayer are calculated by different methods. These profiles allow us to address two central and unresolved problems in pressure profile calculations: The first problem is that the pressure profile is not uniquely defined since the expression for the local pressure involves an arbitrary choice of an integration contour. We have investigated two different choices leading to the Irving-Kirkwood (IK) and Harasima (H) expressions for the local pressure tensor. For these choices we find that the pressure profile is almost independent of the contour used, which indicates that the local pressure is well defined for a DPPC bilayer in the liquid crystalline phase. This may not be the case for other systems and we therefore suggest that both the IK and H profiles are calculated in order to test the uniqueness of the profile. The second problem is how to include electrostatic interactions in pressure profile calculations when the simulations are conducted without truncating the electrostatic potential, i.e., using the Ewald summation technique. Based on the H expression for the local pressure, we present a method for calculating the contribution to the lateral components of the local pressure tensor from electrostatic interactions evaluated by the Ewald summation technique. Pressure profiles calculated with an electrostatic potential truncation (cutoff) from simulations conducted with Ewald summation are shown to depend on the cutoff in a subtle manner which is attributed to the existence of long-ranged charge ordering in the system. However, the pressure profiles calculated with relatively long cutoffs are qualitatively similar to the Ewald profile for the DPPC bilayer studied here.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Reconciliation of opposing views on membrane–sugar interactions

Heidi Delcomyn Andersen; Lise Arleth; Günther H. Peters; Peter Westh

It is well established that small sugars exert different types of stabilization of biomembranes both in vivo and in vitro. However, the essential question of whether sugars are bound to or expelled from membrane surfaces, i.e., the sign and size of the free energy of the interaction, remains unresolved, and this prevents a molecular understanding of the stabilizing mechanism. We have used small-angle neutron scattering and thermodynamic measurements to show that sugars may be either bound or expelled depending on the concentration of sugar. At low concentration, small sugars bind quite strongly to a lipid bilayer, and the accumulation of sugar at the interface makes the membrane thinner and laterally expanded. Above ∼0.2 M the sugars gradually become expelled from the membrane surface, and this repulsive mode of interaction counteracts membrane thinning. The dual nature of sugar–membrane interactions offers a reconciliation of conflicting views in earlier reports on sugar-induced modulations of membrane properties.


Biophysical Journal | 1996

Theoretical investigation of the dynamics of the active site lid in Rhizomucor miehei lipase.

Günther H. Peters; O.H. Olsen; A. Svendsen; R.C. Wade

Interfacial activation of Rhizomucor miehei lipase is accompanied by a hinge-type motion of a single helix (residues 83-94) that acts as a lid over the active site. Activation of the enzyme involves the displacement of the lid to expose the active site, suggesting that the dynamics of the lid could be of mechanistic and kinetic importance. To investigate possible activation pathways and to elucidate the effect of a hydrophobic environment (as would be provided by a lipid membrane) on the lid opening, we have applied molecular dynamics and Brownian dynamics techniques. Our results indicate that the lipase activation is enhanced in a hydrophobic environment. In nonpolar low-dielectric surroundings, the lid opens in approximately 100 ns in the BD simulations. In polar high-dielectric (aqueous) surroundings, the lid does not always open up in simulations of up to 900 ns duration, but it does exhibit some gating motion, suggesting that the enzyme molecule may exist in a partially active form before the catalytic reaction. The activation is controlled by the charged residues ARG86 and ASP91. In the inactive conformation, ASP91 experiences repulsive forces and pushes the lid toward the open conformation. Upon activation ARG86 approaches ASP61, and in the active conformation, these residues form a salt bridge that stabilizes the open conformation.


Journal of Chemical Physics | 2004

The hydrophobic effect: Molecular dynamics simulations of water confined between extended hydrophobic and hydrophilic surfaces

Morten Jensen; Ole G. Mouritsen; Günther H. Peters

Structural and dynamic properties of water confined between two parallel, extended, either hydrophobic or hydrophilic crystalline surfaces of n-alkane C(36)H(74) or n-alcohol C(35)H(71)OH, are studied by molecular dynamics simulations. Electron density profiles, directly compared with corresponding experimental data from x-ray reflectivity measurements, reveal a uniform weak de-wetting characteristic for the extended hydrophobic surface, while the hydrophilic surface is weakly wetted. These microscopic data are consistent with macroscopic contact angle measurements. Specific water orientation is present at both surfaces. The ordering is characteristically different between the surfaces and of longer range at the hydrophilic surface. Furthermore, the dynamic properties of water are different at the two surfaces and different from the bulk behavior. In particular, at the hydrophobic surface, time-correlation functions reveal that water molecules have characteristic diffusive behavior and orientational ordering due to the lack of hydrogen bonding interactions with the surface. These observations suggest that the altered dynamical properties of water in contact with extended hydrophobic surfaces together with a partial drying of the surfaces are more indicative of the hydrophobic effect than structural ordering, which we suggest to be independent of surface topology.


Biophysical Journal | 2003

Ligand-Induced Conformational Changes: Improved Predictions of Ligand Binding Conformations and Affinities

Thomas M. Frimurer; Günther H. Peters; Lars Fogh Iversen; Henrik Sune Andersen; Niels Peter Hundahl Møller; Ole Hvilsted Olsen

A computational docking strategy using multiple conformations of the target protein is discussed and evaluated. A series of low molecular weight, competitive, nonpeptide protein tyrosine phosphatase inhibitors are considered for which the x-ray crystallographic structures in complex with protein tyrosine phosphatase 1B (PTP1B) are known. To obtain a quantitative measure of the impact of conformational changes induced by the inhibitors, these were docked to the active site region of various structures of PTP1B using the docking program FlexX. Firstly, the inhibitors were docked to a PTP1B crystal structure cocrystallized with a hexapeptide. The estimated binding energies for various docking modes as well as the RMS differences between the docked compounds and the crystallographic structure were calculated. In this scenario the estimated binding energies were not predictive inasmuch as docking modes with low estimated binding energies corresponded to relatively large RMS differences when aligned with the corresponding crystal structure. Secondly, the inhibitors were docked to their parent protein structures in which they were cocrystallized. In this case, there was a good correlation between low predicted binding energy and a correct docking mode. Thirdly, to improve the predictability of the docking procedure in the general case, where only a single target protein structure is known, we evaluate an approach which takes possible protein side-chain conformational changes into account. Here, side chains exposed to the active site were considered in their allowed rotamer conformations and protein models containing all possible combinations of side-chain rotamers were generated. To evaluate which of these modeled active sites is the most likely binding site conformation for a certain inhibitor, the inhibitors were docked against all active site models. The receptor rotamer model corresponding to the lowest estimated binding energy is taken as the top candidate. Using this protocol, correct inhibitor binding modes could successfully be discriminated from proposed incorrect binding modes. Moreover, the ranking of the estimated ligand binding energies was in good agreement with experimentally observed binding affinities.


Journal of Physics: Condensed Matter | 2006

Activation of interfacial enzymes at membrane surfaces

Ole G. Mouritsen; Thomas Lars Andresen; Avi Halperin; Per Lyngs Hansen; Ask F. Jakobsen; Uffe Bernchou Jensen; Morten Ø. Jensen; Kent Jørgensen; Thomas Kaasgaard; Chad Leidy; Adam Cohen Simonsen; Günther H. Peters; Matthias Weiss

A host of water-soluble enzymes are active at membrane surfaces and in association with membranes. Some of these enzymes are involved in signalling and in modification and remodelling of the membranes. A special class of enzymes, the phospholipases, and in particular secretory phospholipase A(2) (sPLA(2)), are only activated at the interface between water and membrane surfaces, where they lead to a break-down of the lipid molecules into lysolipids and free fatty acids. The activation is critically dependent on the physical properties of the lipid-membrane substrate. A topical review is given of our current understanding of the physical mechanisms responsible for activation of sPLA(2) as derived from a range of different experimental and theoretical investigations.


Journal of Medicinal Chemistry | 2010

Liposomal formulation of retinoids designed for enzyme triggered release.

Palle Jacob Pedersen; Sidsel K. Adolph; Arun Kumar Subramanian; Ahmad Arouri; Thomas Lars Andresen; Ole G. Mouritsen; Robert Madsen; Mogens Madsen; Günther H. Peters; Mads Hartvig Clausen

The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesized four different retinoid phospholipid prodrugs and shown that they form particles in the liposome size region with average diameters of 94-118 nm. Upon subjection to phospholipase A(2), the lipid prodrugs were hydrolyzed, releasing cytotoxic retinoids and lysolipids. The formulated lipid prodrugs displayed IC(50) values in the range of 3-19 microM toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A(2), while no significant cell death was observed in the absence of the enzyme.


Angewandte Chemie | 2009

Drug Delivery by an Enzyme‐Mediated Cyclization of a Lipid Prodrug with Unique Bilayer‐Formation Properties

Lars Linderoth; Günther H. Peters; Robert Madsen; Thomas Lars Andresen

Special delivery: Liposomal drug-delivery systems in which prodrugs are activated specifically by disease-associated enzymes have great potential for the treatment of severe diseases, such as cancer. A new type of phospholipid-based prodrug has the ability to form stable small unilamellar vesicles (see picture). Activation of the prodrug vesicles by the enzyme sPLA(2) initiates a cyclization reaction, which leads to the release of the drug.

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Flemming Y. Hansen

Technical University of Denmark

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Jens Abildskov

Technical University of Denmark

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Ole G. Mouritsen

University of Southern Denmark

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Pernille Harris

Technical University of Denmark

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Thomas Lars Andresen

Technical University of Denmark

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Kent Jørgensen

Technical University of Denmark

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