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Until recently proteins were considered as nature’s robots performing both unique chemical transformations or specifically interacting with their cognate binding partners under environmental conditions suitable for living organisms. Common understanding is that these functionalities rely on the existence of stably folded protein scaffolds. This structure-function paradigm, however, has been put in question: it is now acknowledged that an increasing number of proteins are lacking stably folded tertiary structures and that this intrinsic flexibility contributes to their biological functionality. The emerging picture is that proteins have evolved to substantially increase the diversity of their conformational ensembles and that even in seemingly random-coil-like disordered proteins there is a hidden structural simplicity that needs to be addressed by appropriate experimental techniques and theoretical concepts which grasp the essential properties of the underlying structural components.
A hallmark of our research is the integrative application of a novel computational biology concept (meta-structure concept) and information-rich NMR spectroscopy directed towards a better understanding of the underlying mechanisms of important biological problems. Finally, as much of protein function is predicated on dynamics, we are developing novel methodological approaches which combine biochemistry, bioorganic chemistry and NMR spectroscopy to unravel the microscopic details of functionally important protein plasticity with potential applications also in drug development programs.
Robert Konrat studied Chemistry in Graz, Austria, and did postdoctoral research at the Université de Lausanne and University of Toronto. He held faculty positions at the University of Innsbruck and visiting professorships at the École Normale Supérieur, Paris, France, University of Barcelona, Spain and the University of California, San Diego, USA.
Correlated structural fluctuations in IDPs are probed by a novel NMR technique developed in our laboratory employing cross-correlated paramagnetic spin relaxation. An application to the Osteopontin-Heparin complex revealed unprecedented details of structural adaptations upon polysaccharide binding.
A novel technique was developed to probe protein-receptor binding in living cells. By combining advanced cell biology and sophisticated NMR techniques unique information about receptor-binding sites can be obtained that allows the determination of IDP-receptor complexes in native environments.
A central theme of the laboratory is to overcome the dichotomy of globular proteins and IDPs. To this end, we have developed computational and NMR techniques that unravel hidden structural compaction in IDPs. The IDP-region of CFTR partly exists in a compact state that facilitates binding to the structured nucleotide-binding domain.
We have developed a versatile prediction method of identifying protein targets and the identification of novel chemical scaffolds for protein targets exclusively based on primary sequence information of the protein (meta-structure) or a 2D representation of the small molecule (Shannon-Entropy Descriptor, SHED).
Our integrated methods platform offers exciting possibilities in biomedical research: identification of novel drugs and their targets, drug repurposing, pathway and mode of action analysis of drugs. Finally, preliminary big data analysis of existing drugs has revealed a surprising hidden relationship among different disease areas.
Toward Rational Fragment-Based Lead Design without 3D Structures.
Henen, Morkos A; Coudevylle, Nicolas; Geist, Leonhard; Konrat, Robert
Allosteric Communication in the KIX Domain Proceeds through Dynamic Repacking of the Hydrophobic Core.
Brüschweiler, Sven; Konrat, Robert; Tollinger, Martin
Compensatory adaptations of structural dynamics in an intrinsically disordered protein complex.
Kurzbach, Dennis; Schwarz, Thomas C; Platzer, Gerald; Höfler, Simone; Hinderberger, Dariush; Konrat, Robert
Project title: "NMR investigations of the hyperphosphorylated IDP Osteopontin" (P28359)
Project title: “Structural Dynamics of IDPs probed by Cross-Correlated NMR Spin Relaxation" (P 28359)
LS17-008, Structure Zoom (as Co-PI with Christian Becker)
ITN: FLUOR21 participant
2016-2019: The Group Konrat participates in the special Doctoral Program "Integrative Structural Biology" reviewed and funded by the Austrian Science Fund FWF.
Novartis, Boehringer-Ingelheim, UCB, Alkahest, IDPharma, Everpharma, Neuropore
Description: The scientists will primarily investigate protein structure, which is crucial for the development of new therapeutic methods for a great variety of diseases ranging from Alzheimer’s and infectious diseases to cancer. This renders it a most valuable tool in biomedical research. In order to gain new insights into protein structure, function and interactions that could potentially be translated into new therapies, the researchers will employ a combination of bioinformatics, protein production and high-end biophysical and structural biology techniques. The collected information will ultimately be combined in an information pipeline for both research and biotechnology.