title: Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2.
abstract: We report the crystal structure of a 40 mer mirror-image RNA oligonucleotide completely built from nucleotides of the non-natural L-chirality in complex with the pro-inflammatory chemokine L-CLL2 (monocyte chemoattractant protein-1), a natural protein composed of regular L-amino acids. The L-oligonucleotide is an L-aptamer (a Spiegelmer) identified to bind L-CCL2 with high affinity, thereby neutralizing the chemokine's activity. CCL2 plays a key role in attracting and positioning monocytes; its overexpression in several inflammatory diseases makes CCL2 an interesting pharmacological target. The PEGylated form of the L-aptamer, NOX-E36 (emapticap pegol), already showed promising efficacy in clinical Phase II studies conducted in diabetic nephropathy patients. The structure of the L-oligonucleotide[Symbol: see text]L-protein complex was solved and refined to 2.05 Å. It unveils the L-aptamer's intramolecular contacts and permits a detailed analysis of its structure-function relationship. Furthermore, the analysis of the intermolecular drug-target interactions reveals insight into the selectivity of the L-aptamer for certain related chemokines.
authors.affiliation: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany.|Center for Free-Electron Laser Science, Deutsches Elektronen Synchrotron-DESY, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Oberthür
authors.affiliation: NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: John
authors.identifier: http://orcid.org/0000-0001-8161-4335
authors.initials: J
authors.lastname: Achenbach
authors.affiliation: Institute of Protein Research, RAS, Pushchino, Moscow Region 142290, Russian Federation.
authors.forename: Azat
authors.initials: A
authors.lastname: Gabdulkhakov
authors.affiliation: NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Buchner
authors.affiliation: NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maasch
authors.affiliation: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Falke
authors.affiliation: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Rehders
authors.affiliation: NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.affiliation: Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Betzel
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000378:metabolism; D018932:Chemokine CCL2 / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D006801:Humans; D008958:Models, Molecular; D011994:Recombinant Proteins
chemical_list: D052157:Aptamers, Nucleotide; D018932:Chemokine CCL2; C541611:NOX-E36 aptamer; D011994:Recombinant Proteins