BIOTEC: Pisabarro

Structural Bioinformatics - Pisabarro

Computational Approaches to Functional Genomics and Rational Engineering.

Our group develops and applies computational strategies for functional genome annotation and rational engineering as strategies for target/drug discovery and biotechnology innovation.
By applying structure-based computational methods, molecular modeling and computer simulation techniques we try to decipher the relationships between protein structure and function in order to understand the molecular basis of protein recognition, which will allow us to unravel protein function and to rationally intervene with it. Our current research focuses on the discovery and functional characterization of novel proteins, the rational engineering of proteins with improved functional properties, and de novo design of molecular scaffolds for a variety of biotechnological and biomedical applications.

Research

Computational approaches to functional genomics and rational engineering for target/drug discovery and biotechnology innovation.

Integrative bioinformatics for structure-based functional annotation of uncharacterized proteins and new target discovery

From cellular phenotypes to structure-based functional characterization of novel genes obtained from genome-wide RNAi screenings in human cells:

We develop computational tools for integration and analysis of data for automatic protein functional annotation. We develop computational structure-based approaches to predict and/or confirm structural features of non-characterized proteins where classical sequence-based methods fail. We use computer modelling and simulation tools to build detailed 3D atomic models of the uncharacterized proteins and their complexes to derive hypotheses that, in close collaboration with the experimentalist, help to predict and understand their function and networks.

Discovery and functional annotation of novel proteins using 3D descriptors:

We combine fold recognition approaches and the development structure-based functional descriptors (3D descriptors) of protein folds for automatic genome-wide discovery of remote homologues members of different structural protein families. We are working on the identification and functional characterization of novel human proteins involved in inflammatory, immune and cancer processes that cannot be characterized by sequence -based methods due to their low or not existing sequence similarity to others.

Computational studies on molecular recognition

Detailed characterization and classification of protein interfaces and implications for protein function and ligand design:

We are working on the development of computational tools to extract, analyze and classify protein interaction information from the PDB in an automatic and comparative fashion. These methods help to obtain an accurate description of protein interfaces, which is needed in order to gain insight about protein function and to be able to properly characterize protein networks. We have built SCOWLP (Structural Characterization Of Water, Ligands and Proteins), a web-based relational database that allows detailed characterization (i.e. physicochemical properties) and visualization of all protein interfaces contained in the PDB, including proteins, peptidic ligands, DNA, saccharides and interface water molecules as descriptors of protein interfaces. SCOWLP is available at (www.scowlp.org)

SCOWLP: A web-based database developed in our group for detailed characterization, classification and visualization of protein interfaces. SCOWLP includes peptide-protein, DNA-protein and saccharide-protein interactions, and also all interfacial water-mediated interactions in PDB. (www.scowlp.org)

Analysis of the role of solvent in protein recognition:

We carry out studies that highlight the importance of including solvent in protein interface definition and consequently in protein interaction studies. Water molecules can play an important role in interaction conservation in protein interfaces by allowing sequence variability. Our studies help to deepen our understanding of the physico?chemical nature underlying protein interactions and strengthen the idea of including solvent to qualitatively improve the accuracy of folding, docking and rational design algorithms.

Comparative analysis and prediction of protein-protein and protein-ligand interactions.

Development of tools for structure-based functional annotation of proteins

Rational engineering and de novo design for biotechnological and/or medical applications

Rational engineering of enzymes with improved anti-HIV functional properties:

We collaborate with experimental groups in the generation of new DNA recombinases with improved properties to excise HIV from infected human cells. The group of Prof. Buchholz (MPI CBG/TUD) uses in vitro evolution strategies to evolve DNA recombinases, which have been recently shown to be able to excise a sub-classe of HIV from human HIV infected cells (Sarkar et al, Science 2007; DOI: 10.1126/science.1141453). New recombinases are being engineered with improved properties, and we use computational approaches to rationalize the molecular recognition of these enzymes with the aim of establishing the bases for their structure-function relationships and to be able to rationally design evolved DNA recombinases with the desired properties of stability and specificity for different DNA sequences.

De novo rational design of molecular scaffolds mimicking protein interactions for specific interference in cell signaling processes:

We apply molecular modelling and computer simulation techniques for designing molecules with pharmacological/biotechnological interest. On one hand, we make use of scaffolds that are available in nature and rationally modify them in order to improve their properties in terms of stability, affinity and specificity. On the other hand, we de novo design scaffolds that mimic natural protein 3D templates involved in interactions of pharmacological relevance.

Rational engineering of biomaterials for tissue regeneration:

GAGs (glycosaminoglycans) are common constituents of cell surfaces and extracellular matrices, and their interactions with a wide variety of molecules such as growth factors and cytokines play a prominent role in basic biological phenomena like cell adhesion, migration, proliferation and differentiation. Thanks to these biocharacteristics, attachment of GAGs to biomaterials offers a great opportunity to modulate tissue response and create an appropriate environment for cellular signalling, both important issues in tissue engineering and regeneration. In close collaboration with experimentalists, we work on the characterization of the structural requirements for protein-GAG binding to understand the molecular basis of the affinity and specificity governing these interactions. We apply computational modelling and simulation techniques to understand the hetereogeneity of the GAG component and to study structural and physical characteristics of GAGs in the context of their interaction with their biological binding-partners. Our studies help in the design of building blocks for chemical and modular synthesis of GAGs-derivatives and matrix scaffolds in biomaterials to promote bio-specific cell behaviour. This work is funded by the German Research Council SFB-TRR 67 TransRegio 67

Publications

Tomczak, A.; Sontheimer, J.; Drechsel, D.; Hausdorf, R.; Gentzel, M.; Shevchenko, A.; Eichler, S.; Fahmy, K.; Buchholz, F.; Pisabarro, M. T. "3D profile-based approach to proteome-wide discovery of novel human chemokines."
PLoS One, in press (2012).

Hawkins, J. C.; Zhu, H.; Teyra, J. ; Pisabarro, M. T. "Reduced false positives in PDZ binding prediction using sequence and structural descriptors ."
IEEE/ACM Transactions on Computational Biology and Bioinformatics, in press (2012).

Schlorke, D.; Thomas, L.; Samsonov, S. A.; Huster, D.; Arnhold, J.; Pichert, A. "The influence of glycosaminoglycans on IL-8-mediated functions of neutrophils."
Carbohydrate Research, in press (2012).

Teyra, J.; Samsonov, S.A.; Schreiber, S.; Pisabarro, M. T. "SCOWLP update: 3D classification of protein-protein, -peptide, -saccharide and -nucleic acid interactions, and structure-based binding inferences across folds."
BMC Bioinformatics,12:398(2011).

Pichert, A.; Samsonov, S.A.; Theisgen, S.; Thomas, L.; Baumann, L.; Schiller, J.; Beck-Sickinger, A.G.; Huster, D.; Pisabarro, M.T." Characterization of the Interaction of Interleukin-8 with Hyaluronan, Chondroitin Sulfate, Dermatan Sulfate, and Their Sulfated Derivatives by Spectroscopy and Molecular Modelling."
Glycobiology, 22(1):134-145 (2011).

Samsonov, S.A.; Teyra, J.; Pisabarro, M. T. "Docking glycosaminoglycans to proteins: analysis of solvent inclusion".
Journal of Computer-Aided Molecular Design, 25(5):477-89 (2011).

Tomczak, A. and Pisabarro, M. T. "Identification of CCR2-binding features in Cytl1 by a CCL2-like chemokine model."
PROTEINS: Structure, Function, and Bioinformatics, 79(4):1277-1292 (2011).

Teyra, J.; Hawkins, J.; Zhu, H.; Pisabarro, M. T. "Studies on the inference of protein binding regions across fold space based on structural similarities."
PROTEINS: Structure, Function, and Bioinformatics, 79(2):499-508 (2011).

Zhu, H. and Pisabarro, M. T. "MSPocket: An Orientation Independent Algorithm for the Detection of Ligand Binding Pockets"
Bioinformatics, 27(3):351-8 (2011).

Slabicki, M.; Theis, M.; Krastev, D.; Samsonov, S.; Mundwiller, E.; Junqueira, M.; Paszkowski-Rogacz, M.; Teyra, J.; Heninger, A-K.; Poser, I.; Prieur, F.; Truchetto, J.; Confavreux, C.; Marelli, C.; Durr, A.; Camdessanche, J. P.; Brice, A.; Shevchenko, F.; Pisabarro, M. T.; Stevanin, G.; Buchholz, F. "A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia."
PLoS Biology, 8(6):e1000408 (2010)

Paszkowski-Rogacz, M.; Slabicki, M.; Pisabarro, M. T.; Buchholz, F. "PhenoFam - gene set enrichment analysis through protein structural information".
BMC Bioinformatics, 11:254 (2010)

Palencia A.; Camara-Artigas A.; Pisabarro M.T.; Martinez J.C.; Luque I. "The role of interfacial water molecules in proline-rich ligand recognition by the SH3 domain of Abl."
J Biol Chem. 285(4):2823-33 (2010)

Samsonov, S.A.; Salwiczek, M.; Anders, G.; Koksch, B.; Pisabarro, M. T. "Fluorine in protein environments: A QM and MD study".
J. Phys. Chem. B. 113(51)16400-8 (2009)

Samsonov, S.A.; Teyra, J.; Anders, G.; Pisabarro, M. T. "Analysis of the impact of solvent on contacts prediction in proteins".
BMC Struct. Biol., 9(1):22  (2009)

Salwiczek, M.; Samsonov, S.; Vagt, T.; Nyakatura, E.; Fleige, E.; Numata, J.; Cölfen, H.; Pisabarro, M. T.; Koksch, B. "Position Dependent Effects of Fluorinated Amino Acids on Hydrophobic Core Formation of a Heterodimeric Coiled Coil".
Chem. Eur. J., 15(31):7628-36  (2009)

Ding, L.; Paszkowski-Rogacz, M.; Nitzsche, A.; Slabicki, M.; Heninger, A-K; Kittler, R. Junqueira, M.; Shevchenko, A.; Schulz, H.; Hubner, N.; Doss, M. X.; Sachinidis, A.; Hescheler, J.; Iacone, R.; Anastassiadis, K.; Stewart, F.; Pisabarro, M. T.; Caldarelli, A.; Poser, I.; Theis, M.; Buchholz, F. "A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity".
Cell Stem Cell, 4(5):403-15  (2009)

Theis, M.; Slabicki, M.; Junqueira, M.; Paszkowski-Rogacz, M.; Sontheimer, J.; Kittler, R.; Heninger, A.; Kruusmaa, K.; Poser, I.; Hyman, A.; Pisabarro, M. T.; Gstaiger, M.; Aebersold, R.; Shevchenko, A.; Buchholz, F. "Comparative Profiling Identifies C13orf3 as a Novel Component of the Ska Complex Required for Mammalian Cell Division".
EMBO J., 28(10):1453-65 (2009)

Vagt, T.; Jäckel, C.; Samsonov, S.; Pisabarro, M. T.; Koksch, B. "Selection of a buried salt bridge by phage display".
Bioorg. Med. Chem. Lett., 19(14):3924-7 (2009)

Samsonov, S.; Teyra, J.; Pisabarro, M. T. "A molecular dynamics approach to study the importance of solvent in protein interactions".
PROTEINS: Structure, Function, and Bioinformatics, 73(2):515-25 (2008)

Baldauf, C.; Pisabarro, M. T. "Stable Hairpins with ?-Peptides - A Route to Tackle Protein-Protein Interactions".
J. Phys. Chem. B,112(25):7581-91(2008)

Teyra, J.; Paszkowski-Rogacz, M.; Anders, G.; Pisabarro, M. T. "SCOWLP classification: Structural comparison and analysis of protein binding regions"
BMC Bioinformatics, 9:9  (2008)

Lättig, J.; Böhl, M.; Fischer, P.; Tischer, S.; Tietböhl, C.; Menschikowski, M.; Gutzeit, H. O.; Metz, P.; Pisabarro, M. T. ?Mechanism of Inhibition of Human Secretory Phospholipase A2 by Flavonoids ? Rationale for Lead Design?.
Journal of Computer-Aided Molecular Design, 21(8):473-83 (2007)

Scheike, J.; Baldauf, C.; Spengler, J.; Albericio, F.; Pisabarro, M. T.; Koksch, B. "Amide-to-ester substitution in coiled coils: the effect of removing hydrogen bonds on protein structure".
Angewandte Chemie, 46(41):7766-7769 (2007)

Teyra, J. and Pisabarro, M. T. "Characterization of Interfacial Solvent in Protein Complexes and Contribution of Wet Spots to the Interface Description"
PROTEINS: Structure, Function, and Bioinformatics, 67, 1087-1095 (2007)

Pisabarro, M. T.; Leung, B; Kwong, M.; Corpuz, R.; Frantz, G. D.; Chiang, N.; Vandlen, R.; Diehl, L. J.; Skelton, N.; Eaton, D.; Schmidt, K. N. ?Novel Human Dendritic Cell- and Monocyte-attracting Chemokine-like Protein Identified by Fold Recognition Methods"
Journal of Immunology, 176, 2069-2073 (2006)

Teyra, J.; Doms, A.; Schroeder, M.; Pisabarro, M. T. "SCOWLP: a web-based database for detailed characterization and visualization of protein interfaces"
BMC Bioinformatics, 7:104  (2006)

Kittler, R.; Putz, G.; Pelletier, L.; Poser, I.; Heninger, A. K.; Drechsel, D.; Fischer, S.; Konstantinova, I.; Habermann, B.; Grabner, H.; Yaspo, M. L.; Himmelbauer, H.; Korn, B.; Neugebauer, K; Pisabarro, M. T.; Buchholz, F. ?An endoribonuclease- prepared siRNA screen in human cells identifies genes essential for cell division?.
Nature, 432, 1036-1040 (2004)

Cobos, E. S.; Pisabarro M.T., Vega, C., Lacroix E., Serrano L.; Ruiz-Sanz, J. Martinez J. C. ?A miniprotein scaffold used to assemble the PPII binding epitope recognized by SH3 domains?.
J. Mol. Biol., 342(1):355-365 (2004)

Leung, B.; Kwong, M.; Pisabarro, M. T.; Schmidt K. N. ?Dendritic cell / monocyte-attracting chemokine DMC is a novel chemokine that has a potential role in homeostasis?.
Clinical and Investigative Medicine, 27(4), 2581 (2004)

Skelton N.J., Koehler M.F., Zobel K., Wong W.L., Yeh S., Pisabarro M.T., Yin J.P., Lasky L.A., Sidhu S.S. ?Origins of PDZ domain ligand specificity. Structure determination and mutagenesis of the Erbin PDZ?.
J. Biol. Chem., 278(9):7645-7654 (2003)

Camenisch, G., Pisabarro M.T., Sherman, D., Kowalski, J., Nagel, M., Hass, P., Gurney, A., Bodary, S.C., Liang, X.H., Clark, K.R., Beresini, M.H., Ferrara, N., Gerber, H.P. ?ANGPTL3 stimulates endothelial cell adhesion and migration via integrin ?V?3 and induces blood vessel formation in vivo?.
J. Biol. Chem., 277(19)17281-17290 (2002)

Pisabarro, M. T.; Leung, B; Kwong, M.; Corpuz, R.; Vandlen, R.; Gurney, A.; Eaton, D. L.; Schmidt K. N. ?Tissue localization and selectivity for immature dendritic cells and monocytes suggest a role for a novel dendritic cell/monocyte attracting chemokine in homeostasis?.
Journal of Interferon & Cytokine Research, 22(1) 11-36 (2002)

Vucic, D., Deshayes, K., Ackerly, H., Pisabarro, M.T., Kadkhodayan, S., Fairbrother, W.J., Dixit , V.M. ?SMAC negatively regulates the anti-apoptotic activity of ML-IAP?.
J. Biol. Chem., 277(14)12275-12279 (2002)

Wu Y.; Dowbenko D.; Pisabarro M. T.; Dillard-Telm L.; Koeppen H.; Lasky LA. "PTEN2, a golgi-associated testis-specific homologue of the PTEN tumor suppressor lipid phosphatase".
J. Biol. Chem., 276(24),21745-53 (2001)

Skelton, N. J.; Chen, Y. M.; Dubree, N.; Quan, C.; Jackson, D.; Cochran, A.; Zobel, K.; Deshayes, K.; Baca, M.; Pisabarro, M.T.; Lowman, H. B. "Structure- function analysis of a phage display-derived peptide that binds to insulin-like growth factor binding protein 1".
Biochemistry, 40(29), 8487-98 (2001)

Vucic, D.; Stennicke H.; Pisabarro, M.T.; Salvesen, G.; Dixit, V. M. "ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas".
Curr. Biol., 10(21),1359-1366 (2000)

Uren, A. G.; O'Rourke, K.; Aravind, L.; Pisabarro, M.T.; Seshagiri, S.; Koonin, E. V.; Dixit, V. M. "Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma".
Mol. Cell, 6,961-967  (2000)

Gille, H.; Kowalski, J.; Yu, L.; Chen, H.; Pisabarro, M.T.; Davis-Smyth, T.; Ferrara, N. "A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3'-kinase activation and endothelial cell migration".
EMBO J., 19(15), 4064-4073 (2000)

Fuh, G.; Pisabarro, M. T.; Li, Y.; Quan, C.; Lasky, L. A.; Sidhu, S. S. "Analysis of PDZ domain-ligand interactions using carboxy-terminal phage display".
J. Biol. Chem., 275(28), 21486-91 (2000)

Pisabarro, M. T.; Serrano, L.; Wilmanns, M. "Crystal structure of the Abl-SH3 domain complexed with a designed high-affinity peptide ligand. Implications for SH3-ligand interactions".
J. Mol. Biol., 281(3), 513-521 (1998)

Martinez, J. C.; Pisabarro, M. T., and Serrano, L. "Obligatory steps in protein folding".
Nat. Struct. Biol., 5(8), 721-729 (1998)

Wilcock, D., Pisabarro, M.T., Lopez-Hernandez, E., Serrano, L. & Coll, M. "Structure analysis of two CheY mutants: Importance of the hydrogen-bond contribution to protein stability".
Acta Crystalographica D, 54(3), 378-385 (1997)

Pisabarro, M. T. and Serrano, L. "Rational design of specific high-affinity peptide ligands for the Abl-SH3 domain".
Biochemistry, 35(33), 10634-10640 (1996)

Ortiz, A. R.; Pisabarro, M. T.; Gago, F.; Wade, R. C. "Prediction of drug binding affinities by comparative binding energy analysis".
J. Med. Chem., 38, 2681-2691 (1995)

Pisabarro, M. T.; Ortiz, A. R.; Gago, F.; Serrano, L. "Molecular modeling of the interaction of polyproline-based peptides with the abl-SH3 domain: rational modification of the interaction".
Prot. Engineering, 7 (12), 1455-1462 (1994)

Pisabarro, M. T.; Ortiz, A. R.; Serrano, L.; Wade, R. C. "Homology modeling of the abl-SH3 domain".
Proteins, 20, 203-215 (1994)

Pisabarro, M. T.; Ortiz, A. R.; Palomer, A.; Cabré, F.; García, M. L.; Wade, R. C.; Gago, F; Mauleón, D.; Carganíco, G. "Rational modification of a human synovial fluid phospholipase A2 inhibitor leading to enhanced activity".
J. Med.Chem., 37, 337-341 (1994)

Pisabarro, M. T.; Palomer, A.; Ortiz, A. R.; Wade, R. C.; Gago, F.; Mauleon, D.; Garganico, G. "Rational drug design: GRID- and LUDI-based structural modifications of a human synovial fluid phospholipase A2 inhibitor leading to enhanced activity".
J. Mol. Graphics, 12:72 (1994)

Ortiz, A. R.; Pisabarro, M. T.; Gago, F. "Molecular model of the interaction of bee venom phospholipase A2 with manoalide".
J. Med. Chem., 36 , 1866-1879 (1993)

Ortiz, A. R.; Pisabarro, M. T.; Gallego, J.; Gago, F. "Implications of a consensus recognition site for phosphatidylcholine separate from the active site in cobra venom phospholipase A2".
Biochemistry, 31 (11), 2887-96 (1992)

Funding

Klaus Tschira Stiftung

http://www.trr67.de/TRANSREGIO 67

Group Leader short CV

María Teresa (Mayte) Pisabarro

1997: PhD, Structural and Computational Biology, EMBL Heidelberg, Germany
(Boehringer Ingelheim Fonds Fellow)
1997-1998: Postdoctoral, EMBL Heidelberg and UCSF, San Francisco, USA
1998-2002: Group Leader, Protein Engineering, Genentech Inc., San Francisco, USA
2002-2004: Visiting scientist, MPI CBG Dresden, Germany
Since 2004: Group Leader, Structural Bioinformatics, BIOTEC TU Dresden, Germany
Since 2009: Tenure Group Leader, Structural Bioinformatics, BIOTEC TU Dresden, Germany