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Covalent Tethering of Functional Groups to Proteins Kovalentes Anbinden Von Funktionsgruppen an Proteine Fixation Covalente De Groupes Fonctionnels À Des Protéines

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Covalent Tethering of Functional Groups to Proteins Kovalentes Anbinden Von Funktionsgruppen an Proteine Fixation Covalente De Groupes Fonctionnels À Des Protéines (19) TZZ _T (11) EP 2 455 458 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 9/14 (2006.01) C12N 9/86 (2006.01) 07.01.2015 Bulletin 2015/02 C12Q 1/34 (2006.01) G01N 33/50 (2006.01) G01N 33/58 (2006.01) (21) Application number: 11005045.7 (22) Date of filing: 30.01.2004 (54) Covalent tethering of functional groups to proteins Kovalentes Anbinden von Funktionsgruppen an Proteine Fixation covalente de groupes fonctionnels à des protéines (84) Designated Contracting States: (74) Representative: Potter Clarkson LLP AT BE BG CH CY CZ DE DK EE ES FI FR GB GR The Belgrave Centre HU IE IT LI LU MC NL PT RO SE SI SK TR Talbot Street Nottingham, NG1 5GG (GB) (30) Priority: 31.01.2003 US 444094 P 30.05.2003 US 474659 P (56) References cited: US-A- 4 777 269 (43) Date of publication of application: 23.05.2012 Bulletin 2012/21 • KEVIN KA LEUNG CHEUK ET AL: "SYNTHESIS OF OPTICALLY ACTIVE POLY (62) Document number(s) of the earlier application(s) in (PHENYLACETYLENES) CONTAINING AMINO accordance with Art. 76 EPC: ACID PENDANT GROUPS", POLYMERIC 04707032.1 / 1 594 962 MATERIALS SCIENCE AND ENGINEERING. PMSE PREPRINTS, AMERICAN CHEMICAL (73) Proprietor: PROMEGA CORPORATION SOCIETY, US, vol. 82, 1 January 2000 Madison, Wisconsin 53711 (US) (2000-01-01), page 56/57, XP009071552, ISSN: 0743-0515 (72) Inventors: • HYNKOVAK ET AL: "Identification of the catalytic • Wood, Keith, V. triad in the haloalkane dehalogenase from Madison, Sphingomonas paucimobilis UT26", FEBS Wisconsin 53711 (US) LETTERS,ELSEVIER, AMSTERDAM, NL, vol. 446, • Los, Georgyi, V no. 1, 5 March 1999 (1999-03-05) , pages 177-181, Madison XP004259343, ISSN: 0014-5793, DOI: Wisconsin 53711 (US) 10.1016/S0014-5793(99)00199-4 • Bulleit, Robert, F. • ICHIYAMA S ET AL: "Novel catalytic mechanism Verona of nucleophilic substitution by asparagine Wisconsin 53593 (US) residue involving cyanoalanine intermediate • Klaubert, Dieter revealed by mass spectrometric monitoring of an Arroyo Grande, enzyme reaction", JOURNAL OF BIOLOGICAL California 93420 (US) CHEMISTRY, AMERICAN SOCIETY FOR • McDougall, Mark BIOCHEMISTRY AND MOLECULAR BIOLOGY, Arroyo Grande, US, vol. 275, no. 52, 29 December 2000 California 93420 (US) (2000-12-29), pages 40804-40809, XP002301434, • Zimprich, Chad ISSN: 0021-9258, DOI: 10.1074/JBC.M008065200 Stoughton Wisconsin 53589 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 455 458 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 455 458 B1 • KURIHARA T ET AL: "COMPREHENSIVE SITE- Remarks: DIRECTED MUTAGENESIS OF L-2-HALO ACID Thefile contains technical information submitted after DEHALOGENASE TO PROBE CATALYTIC the application was filed and not included in this AMINO ACID RESIDUES", JOURNAL OF specification BIOCHEMISTRY, JAPANESE BIOCHEMICAL SOCIETY / OUP, TOKYO; JP, vol. 117, no. 6, 1 January 1995 (1995-01-01), pages 1317-1322, XP009038319, ISSN: 0021-924X 2 EP 2 455 458 B1 Description Field of the Invention 5 [0001] This invention relates to the field of biochemical assays and reagents. More specifically, this invention relates to mutant proteins covalently linked (tethered) to one or more functional groups and to methods for their use. Background of the Invention 10 [0002] The specific detection of molecules is a keystone in understanding the role of that molecule in the cell. Labels, e.g., those that are covalently linked to a molecule of interest, permit the ready detection of that molecule in a complex mixture. The label may be one that is added by chemical synthesisin vitro or attached in vivo, e.g., via recombinant techniques. For instance, the attachment of fluorescent or other labels onto proteins has traditionally been accomplished by in vitro chemical modification after protein purification (Hermanson, 1996). For in vivo attachment of a label, green 15 fluorescent protein (GFP) from the jellyfish Aequorea victoria can be genetically fused with many host proteins to produce fluorescent chimeras in situ (Tsien, 1998; Chalfie et al., 1998). However, while GFP-based indicators are currently employed in a variety of assays, e.g., measuring pH (Kneen et al., 1998; Llopis et al., 1998; Miesenböck et al., 1998), Ca2+ (Miyawaki et al., 1997; Rosomer et al., 1997), and membrane potential (Siegel et al., 1997), the fluorescence of intrinsically labeled proteins such as GFP is limited by the properties of protein structure, e.g., a limited range of fluoresc ent 20 colors and relatively low intrinsic brightness (Cubitt et al., 1995; Ormö et al., 1996). [0003] To address the deficiencies of GFP labelingin situ, Griffen et al. (1998) synthesized a tight-binding pair of molecular components: a small receptor domain composed of as few as six natural amino acids and a small (< 700 dalton), synthetic ligand that could be linked to various spectroscopic probes or crosslinks. The receptor domain included four cysteines at the i, i + 1, i + 4, and i + 5 positions of an α helix and the ligand was 4’,5’-bis(1,3,2-dithioarsolan-2- 25 yl)fluorescein (FLASH). Griffen et al. disclose that the ligand had relatively few binding sites in nontransfected mammalian cells, was membrane-permeant and was nonfluorescent until it bound with high affinity and specificity to a tetracysteine domain in a recombinant protein, resulting in cells being fluorescently labeled ("FLASH" labeled) with a nanomolar or lower dissociation constant. However, with respect to background binding in cells, Stroffekova et al. (2001) disclose that FLASH-EDT2 binds non-specifically to endogenous cysteine-rich proteins. Furthermore, labeling proteins by FLASH is 30 limited by the range of fluorophores that may be used. [0004] Receptor-mediated targeting methods use genetically encoded targeting sequences to localize fluorophores to virtually any cellular site, provided that the targeted protein is able to fold properly. For example, Farinas et al. (1999) disclose that cDNA transfection was used to target a single-chain antibody (sFv) to a specified site in a cell. Farinas et al. disclose that conjugates of a hapten (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one, phOx) and a fluorescent probe 35 (e.g., BODIPY FI, tetramethylrhodamine, and fluorescein) were bound with high affinity (about 5 nM) to the subcellular site for the sFv in living Chinese hamster ovary cells, indicating that the targeted antibody functioned as a high affinity receptor for the cell-permeable hapten-fluorophore conjugates. Nevertheless, functional sFv expression may be relatively poor in reducing environments. [0005] Thus, what is needed is an improved method to label a desired protein. 40 [0006] Hynkova (1999) FEBS LETTERS, 446 p 177-181 describes the catalytic triad of a dehalogenase from Sphin- gomonas paucimobilis as including residues D101, H272 and E132. Ichiyama (2000) J. Bioll. Chem., 275 p 40804-40809 investigated the catalytic mechanism of a Pseudomonas sp. dehalogenase with mutation of a catalytic residue. Kurihara (1995) J. Biochem. 117, p 1317-1322 also described mutagenesis of catalytic amino acids inPseudomonas a sp. dehalogenase. Yang (1996) Biochemistry 35, pp 10879-10885 discussed the identification of active site residues in a 45 dehalogenase. Summary of the Invention [0007] There is herein described methods, compositions and kits for tethering (linking), e.g., via a covalent or otherwise 50 stable bond, one or more functional groups to a protein of the invention or to a fusion protein (camera) which includes a protein of the invention. A protein of the invention is structurally related to a wild-type (native) hydrolase but comprises at least one amino acid substitution relative to the corresponding wild-type hydrolase and binds a substrate of the corresponding wild-type hydrolase but lacks or has reduced catalytic activity relative to the corresponding wild-type hydrolase (which mutant protein is referred to herein as a mutant hydrolase). The aforementioned tethering occurs, for 55 instance, in solution or suspension, in a cell, on a solid support or at solution/surface interfaces, by employing a substrate for a hydrolase which includes a reactive group and which has been modified to include one or more functional groups. As used herein, a "substrate" includes a substrate having a reactive group and optionally one or more functional groups. As used herein, a "functional group" is a molecule which is detectable or is capable of detection (e.g., a chromophore, 3 EP 2 455 458 B1 fluorophore or luminophore), or can be bound or attached to a second molecule (e.g., biotin, hapten, or a cross-linking group) or includes one or more amino acids, e.g., a peptide or polypeptide including an antibody or receptor, one or more nucleotides, lipids including lipid bilayers, a solid support, e.g., a sedimental particle, and the like. A functional group may have more than one property such as being capable of detection and being bound to another molecule. As 5 used herein a "reactive group" is the minimum number of atoms in a substrate which are specifically recognized by a particular wild-type or mutant hydrolase of the invention. The interaction of a reactive group in a substrate and a wild- type hydrolase results in a product and the regeneration of the wild-type hydrolase. A substrate, may also optionally include a linker, e.g., a cleavable linker. [0008] A substrate useful herein is one which is specifically bound by a mutant hydrolase, and preferably results in a 10 bond formed with an amino acid, e.g., the reactive residue, of the mutant hydrolase which bond is more stable than the bond formed between the substrate and the corresponding amino acid of the wild-type hydrolase.
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