Christian Renner

Bio: Christian Renner is an academic researcher from Max Planck Society. The author has contributed to research in topics: Azobenzene & Protein structure. The author has an hindex of 39, co-authored 102 publications receiving 4313 citations. Previous affiliations of Christian Renner include Deutsche Forschungsgemeinschaft.

Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53.

Abstract: The oncoprotein MDM2 inhibits the tumor suppressor protein p53 by binding to the p53 transactivation domain The p53 gene is inactivated in many human tumors either by mutations or by binding to oncogenic proteins In some tumors, such as soft tissue sarcomas, overexpression of MDM2 inactivates an otherwise intact p53, disabling the genome integrity checkpoint and allowing cell cycle progression of defective cells Disruption of the MDM2/p53 interaction leads to increased p53 levels and restored p53 transcriptional activity, indicating restoration of the genome integrity check and therapeutic potential for MDM2/p53 binding antagonists Here, we show by multidimensional NMR spectroscopy that chalcones (1,3-diphenyl-2-propen-1-ones) are MDM2 inhibitors that bind to a subsite of the p53 binding cleft of human MDM2 Biochemical experiments showed that these compounds can disrupt the MDM2/p53 protein complex, releasing p53 from both the p53/MDM2 and DNA-bound p53/MDM2 complexes These results thus offer a starting basis for structure-based drug design of cancer therapeutics

Ultrafast spectroscopy reveals subnanosecond peptide conformational dynamics and validates molecular dynamics simulation

Abstract: Femtosecond time-resolved spectroscopy on model peptides with built-in light switches combined with computer simulation of light-triggered motions offers an attractive integrated approach toward the understanding of peptide conformational dynamics. It was applied to monitor the light-induced relaxation dynamics occurring on subnanosecond time scales in a peptide that was backbone-cyclized with an azobenzene derivative as optical switch and spectroscopic probe. The femtosecond spectra permit the clear distinguishing and characterization of the subpicosecond photoisomerization of the chromophore, the subsequent dissipation of vibrational energy, and the subnanosecond conformational relaxation of the peptide. The photochemical cis/trans-isomerization of the chromophore and the resulting peptide relaxations have been simulated with molecular dynamics calculations. The calculated reaction kinetics, as monitored by the energy content of the peptide, were found to match the spectroscopic data. Thus we verify that all-atom molecular dynamics simulations can quantitatively describe the subnanosecond conformational dynamics of peptides, strengthening confidence in corresponding predictions for longer time scales.

Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions.

Abstract: Binding proteins for insulin-like growth factors (IGFs) IGF-I and IGF-II, known as IGFBPs, control the distribution, function and activity of IGFs in various cell tissues and body fluids. Insulin-like growth factor-binding protein-5 (IGFBP-5) is known to modulate the stimulatory effects of IGFs and is the major IGF-binding protein in bone tissue. We have expressed two N-terminal fragments of IGFBP-5 in Escherichia coli; the first encodes the N-terminal domain of the protein (residues 1-104) and the second, mini-IGFBP-5, comprises residues Ala40 to Ile92. We show that the entire IGFBP-5 protein contains only one high-affinity binding site for IGFs, located in mini-IGFBP-5. The solution structure of mini-IGFBP-5, determined by nuclear magnetic resonance spectroscopy, discloses a rigid, globular structure that consists of a centrally located three-stranded anti-parallel beta-sheet. Its scaffold is stabilized further by two inside packed disulfide bridges. The binding to IGFs, which is in the nanomolar range, involves conserved Leu and Val residues localized in a hydrophobic patch on the surface of the IGFBP-5 protein. Remarkably, the IGF-I receptor binding assays of IGFBP-5 showed that IGFBP-5 inhibits the binding of IGFs to the IGF-I receptor, resulting in reduction of receptor stimulation and autophosphorylation. Compared with the full-length IGFBP-5, the smaller N-terminal fragments were less efficient inhibitors of the IGF-I receptor binding of IGFs.

Fluoroprolines as Tools for Protein Design and Engineering

Abstract: The preference of the peptidyl-fluoroproline amide bond for the cis or trans conformation in the model compounds N-acetyl-4-fluoroproline methyl esters fully correlates with the thermostability of the related mutants of the model protein barstar. Thus, the (4S)-L-FPro mutants show a higher and the(4R)-L-FPro mutants a lower thermal stability than barstar.

New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

Abstract: This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.

Collagen Structure and Stability

Abstract: Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen—the prototypical collagen fibril—has been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology.

Synthetic molecular motors and mechanical machines.

Abstract: The widespread use of controlled molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular systems, which by and large rely upon electronic and chemical effects to carry out their functions, and the machines of the macroscopic world, which utilize the synchronized movements of smaller parts to perform specific tasks. This is a scientific area of great contemporary interest and extraordinary recent growth, yet the notion of molecular-level machines dates back to a time when the ideas surrounding the statistical nature of matter and the laws of thermodynamics were first being formulated. Here we outline the exciting successes in taming molecular-level movement thus far, the underlying principles that all experimental designs must follow, and the early progress made towards utilizing synthetic molecular structures to perform tasks using mechanical motion. We also highlight some of the issues and challenges that still need to be overcome.

Photoisomerization in different classes of azobenzene

Abstract: Azobenzene undergoes trans → cisisomerization when irradiated with light tuned to an appropriate wavelength. The reverse cis →transisomerization can be driven by light or occurs thermally in the dark. Azobenzene's photochromatic properties make it an ideal component of numerous molecular devices and functional materials. Despite the abundance of application-driven research, azobenzene photochemistry and the isomerization mechanism remain topics of investigation. Additional substituents on the azobenzene ring system change the spectroscopic properties and isomerization mechanism. This critical review details the studies completed to date on the 3 main classes of azobenzene derivatives. Understanding the differences in photochemistry, which originate from substitution, is imperative in exploiting azobenzene in the desired applications.