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Dive into the research topics where Andreas Kreusch is active.

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Featured researches published by Andreas Kreusch.


Nature | 2007

The nuclear receptor LXR is a glucose sensor

Nico Mitro; Puiying A. Mak; Leo Vargas; Cristina Godio; Eric Hampton; Valentina Molteni; Andreas Kreusch; Enrique Saez

The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose. On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue. This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver. In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis. Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. d-Glucose and d-glucose-6-phosphate are direct agonists of both LXR-α and LXR-β. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.


Proceedings of the National Academy of Sciences of the United States of America | 2002

Structural Genomics of the Thermotoga maritima Proteome Implemented in a High-throughput Structure Determination Pipeline

Scott A. Lesley; Peter Kuhn; Adam Godzik; Ashley M. Deacon; Irimpan I. Mathews; Andreas Kreusch; Glen Spraggon; Heath E. Klock; Daniel McMullan; Tanya Shin; Juli Vincent; Alyssa Robb; Linda S. Brinen; Mitchell D. Miller; Timothy M. McPhillips; Mark A. Miller; Daniel Scheibe; Jaume M. Canaves; Chittibabu Guda; Lukasz Jaroszewski; Thomas L. Selby; Marc André Elsliger; John Wooley; Susan S. Taylor; Keith O. Hodgson; Ian A. Wilson; Peter G. Schultz; Raymond C. Stevens

Structural genomics is emerging as a principal approach to define protein structure–function relationships. To apply this approach on a genomic scale, novel methods and technologies must be developed to determine large numbers of structures. We describe the design and implementation of a high-throughput structural genomics pipeline and its application to the proteome of the thermophilic bacterium Thermotoga maritima. By using this pipeline, we successfully cloned and attempted expression of 1,376 of the predicted 1,877 genes (73%) and have identified crystallization conditions for 432 proteins, comprising 23% of the T. maritima proteome. Representative structures from TM0423 glycerol dehydrogenase and TM0449 thymidylate synthase-complementing protein are presented as examples of final outputs from the pipeline.


Protein Science | 2006

Crystal structure of the human TRPV2 channel ankyrin repeat domain

Clare J. McCleverty; Eric Koesema; Ardem Patapoutian; Scott A. Lesley; Andreas Kreusch

TRPV channels are important polymodal integrators of noxious stimuli mediating thermosensation and nociception. An ankyrin repeat domain (ARD), which is a common protein–protein recognition domain, is conserved in the N‐terminal intracellular domain of all TRPV channels and predicted to contain three to four ankyrin repeats. Here we report the first structure from the TRPV channel subfamily, a 1.7 Å resolution crystal structure of the human TRPV2 ARD. Our crystal structure reveals a six ankyrin repeat stack with multiple insertions in each repeat generating several unique features compared with a canonical ARD. The surface typically used for ligand recognition, the ankyrin groove, contains extended loops with an exposed hydrophobic patch and a prominent kink resulting from a large rotational shift of the last two repeats. The TRPV2 ARD provides the first structural insight into a domain that coordinates nociceptive sensory transduction and is likely to be a prototype for other TRPV channel ARDs.


Bioorganic & Medicinal Chemistry Letters | 2005

Crystal structures of human HSP90α-complexed with dihydroxyphenylpyrazoles

Andreas Kreusch; Shulin Han; Achim Brinker; Vicki Zhou; Ha-Soon Choi; Yun He; Scott A. Lesley; Jeremy S. Caldwell; Xiang-ju Gu

Abstract A series of dihydroxyphenylpyrazole compounds were identified as a unique class of reversible Hsp90 inhibitors. The crystal structures for two of the identified compounds complexed with the N-terminal ATP binding domain of human Hsp90α were determined. The dihydroxyphenyl ring of the compounds fits deeply into the adenine binding pocket with the C2 hydroxyl group forming a direct hydrogen bond with the side chain of Asp93. The pyrazole ring forms hydrogen bonds to the backbone carbonyl of Gly97, the hydroxyl group of Thr184 and to a water molecule, which is present in all of the published HSP90 structures. One of the identified compounds (G3130) demonstrated cellular activities (in Her-2 degradation and activation of Hsp70 promoter) consistent with the inhibition of cellular Hsp90 functions.


Acta Crystallographica Section D-biological Crystallography | 2003

Shotgun crystallization strategy for structural genomics: an optimized two-tiered crystallization screen against the Thermotoga maritima proteome.

Rebecca Page; Slawomir K. Grzechnik; Jaume M. Canaves; Glen Spraggon; Andreas Kreusch; Peter Kuhn; Raymond C. Stevens; Scott A. Lesley

As the field of structural genomics continues to grow and new technologies are developed, novel strategies are needed to efficiently crystallize large numbers of protein targets, thus increasing output, not just throughput [Chayen & Saridakis (2002). Acta Cryst. D58, 921-927]. One strategy, developed for the high-throughput structure determination of the Thermotoga maritima proteome, is to quickly determine which proteins have a propensity for crystal formation followed by focused SeMet-incorporated protein crystallization attempts. This experimental effort has resulted in over 320 000 individual crystallization experiments. As such, it has provided one of the most extensive systematic data sets of commonly used crystallization conditions against a wide range of proteins to date. Analysis of this data shows that many of the original screening conditions are redundant, as all of the T. maritima proteins that crystallize readily could be identified using just 23% of the original conditions. It also shows that proteins that contain selenomethionine and are more extensively purified often crystallize in distinctly different conditions from those of their native less pure counterparts. Most importantly, it shows that the two-tiered strategy employed here is extremely successful for predicting which proteins will readily crystallize, as greater than 99% of the proteins identified as having a propensity to crystallize under non-optimal native conditions did so again as selenomethionine derivatives during the focused crystallization trials. This crystallization strategy can be adopted for both large-scale genomics programs and individual protein studies with multiple constructs and has the potential to significantly accelerate future crystallographic efforts.


Structure | 2003

Crystal Structure of the Human Neuropilin-1 b1 Domain

Christian C. Lee; Andreas Kreusch; Daniel McMullan; Ken Ng; Glen Spraggon

Neuropilin-1 (Npn-1) is a type I cell surface receptor involved in a broad range of developmental processes, including axon guidance, angiogenesis, and heterophilic cell adhesion. We have determined the crystal structure of the human Npn-1 b1 domain to 1.9 A. The overall structure resembles coagulation factor V and VIII (F5/8) C1 and C2 domains, exhibiting a distorted jellyroll fold. Details of the structure provide insight to b1 domain regions responsible for ligand binding and facilitate rationalization of existing biochemical binding data. A polar cleft formed by adjacent loops at one end of the molecule in conjunction with flanking electronegative surfaces may represent the binding site for the positively charged tails of semaphorins and VEGF(165). The nature of the cell adhesion binding site of the b1 domain can be visualized in context of the structure.


Proteins | 2002

Crystal structure of thy1, a thymidylate synthase complementing protein from Thermotoga maritima at 2.25 Å resolution

Peter Kuhn; Scott A. Lesley; Irimpan I. Mathews; Jaume M. Canaves; Linda S. Brinen; Xiaoping Dai; Ashley M. Deacon; Marc André Elsliger; Said Eshaghi; Ross Floyd; Adam Godzik; Carina Grittini; Slawomir K. Grzechnik; Chittibabu Guda; Keith O. Hodgson; Lukasz Jaroszewski; Cathy Karlak; Heath E. Klock; Eric Koesema; John M. Kovarik; Andreas Kreusch; Daniel McMullan; Timothy M. McPhillips; Mark A. Miller; Mitchell D. Miller; Andrew T. Morse; Kin Moy; Jie Ouyang; Alyssa Robb; Kevin Rodrigues

Peter Kuhn, Scott A. Lesley, Irimpan I. Mathews, Jaume M. Canaves, Linda S. Brinen, Xiaoping Dai, Ashley M. Deacon, Marc A. Elsliger, Said Eshaghi, Ross Floyd, Adam Godzik, Carina Grittini, Slawomir K. Grzechnik, Chittibabu Guda, Keith O. Hodgson, Lukasz Jaroszewski, Cathy Karlak, Heath E. Klock, Eric Koesema, John M. Kovarik, Andreas T. Kreusch, Daniel McMullan, Timothy M. McPhillips, Mark A. Miller, Mitchell Miller, Andrew Morse, Kin Moy, Jie Ouyang, Alyssa Robb, Kevin Rodrigues, Thomas L. Selby, Glen Spraggon, Raymond C. Stevens, Susan S. Taylor, Henry van den Bedem, Jeff Velasquez, Juli Vincent, Xianhong Wang, Bill West, Guenter Wolf, John Wooley, and Ian A. Wilson* The Joint Center for Structural Genomics Stanford Synchrotron Radiation Laboratory, Stanford University, Menlo Park, California The Genomics Institute of Novartis Foundation, San Diego, California The San Diego Supercomputer Center, La Jolla, California The University of California, San Diego, La Jolla, California The Scripps Research Institute, La Jolla, California


Acta Crystallographica Section D-biological Crystallography | 2002

Computational analysis of crystallization trials.

Glen Spraggon; Scott A. Lesley; Andreas Kreusch; John P. Priestle

A system for the automatic categorization of the results of crystallization experiments generated by robotic screening is presented. Images from robotically generated crystallization screens are taken at preset time intervals and analyzed by the computer program Crystal Experiment Evaluation Program (CEEP). This program attempts to automatically categorize the individual crystal experiments into a number of simple classes ranging from clear drop to mountable crystal. The algorithm first selects features from the images via edge detection and texture analysis. Classification is achieved via a self-organizing neural net generated from a set of hand-classified images used as a training set. New images are then classified according to this neural net. It is demonstrated that incorporation of time-series information may enhance the accuracy of classification. Preliminary results from the screening of the proteome of Thermotoga maritima are presented showing the utility of the system.


ACS Medicinal Chemistry Letters | 2012

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Pam Albaugh; Yi Fan; Yuan Mi; Fangxian Sun; Francisco Adrian; Nanxin Li; Yong Jia; Yelena Sarkisova; Andreas Kreusch; Tami Hood; Min Lu; Guoxun Liu; Shenlin Huang; Zuosheng Liu; Jon Loren; Tove Tuntland; Donald S. Karanewsky; H. Martin Seidel; Valentina Molteni

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.


Journal of Molecular Biology | 2003

Structure analysis of peptide deformylases from streptococcus pneumoniae,staphylococcus aureus, thermotoga maritima, and pseudomonas aeruginosa: snapshots of the oxygen sensitivity of peptide deformylase

Andreas Kreusch; Glen Spraggon; Chris C. Lee; Heath E. Klock; Daniel McMullan; Ken Ng; Tanya Shin; Juli Vincent; Ian Warner; Christer Ericson; Scott A. Lesley

Peptide deformylase (PDF) has received considerable attention during the last few years as a potential target for a new type of antibiotics. It is an essential enzyme in eubacteria for the removal of the formyl group from the N terminus of the nascent polypeptide chain. We have solved the X-ray structures of four members of this enzyme family, two from the Gram-positive pathogens Streptococcus pneumoniae and Staphylococcus aureus, and two from the Gram-negative bacteria Thermotoga maritima and Pseudomonas aeruginosa. Combined with the known structures from the Escherichia coli enzyme and the recently solved structure of the eukaryotic deformylase from Plasmodium falciparum, a complete picture of the peptide deformylase structure and function relationship is emerging. This understanding could help guide a more rational design of inhibitors. A structure-based comparison between PDFs reveals some conserved differences between type I and type II enzymes. Moreover, our structures provide insights into the known instability of PDF caused by oxidation of the metal-ligating cysteine residue.

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Daniel McMullan

Genomics Institute of the Novartis Research Foundation

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Heath E. Klock

Genomics Institute of the Novartis Research Foundation

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Eric Koesema

Genomics Institute of the Novartis Research Foundation

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Scott A. Lesley

Genomics Institute of the Novartis Research Foundation

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Peter Kuhn

University of Southern California

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Ashley M. Deacon

SLAC National Accelerator Laboratory

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