Structure-Based Design of Inhibitors Selective for Human Proteasome beta 2c or beta 2i Subunits
Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the beta 1c, beta 1i, beta 5c, and beta 5i subunits exploit the differences in the substrate-binding channels identified by X-...
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| Published in | Journal of medicinal chemistry Vol. 62; no. 3; pp. 1626 - 1642 |
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| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Amer Chemical Soc
14.02.2019
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| Abstract | Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the beta 1c, beta 1i, beta 5c, and beta 5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting beta 2c or beta 2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the beta 2c- and beta 2i-selective-compounds LU-002c (4; IC50 beta 2c: 8 nM, IC50 beta 2i/beta 2c: 40-fold) and LU-002i (5; IC50 beta 2i: 220 nM, IC50 beta 2c/beta 2i: 45-fold), respectively. Co-crystal structures with beta 2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of beta 2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors. |
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| AbstractList | Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the beta 1c, beta 1i, beta 5c, and beta 5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting beta 2c or beta 2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the beta 2c- and beta 2i-selective-compounds LU-002c (4; IC50 beta 2c: 8 nM, IC50 beta 2i/beta 2c: 40-fold) and LU-002i (5; IC50 beta 2i: 220 nM, IC50 beta 2c/beta 2i: 45-fold), respectively. Co-crystal structures with beta 2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of beta 2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors. |
| Author | Heinemeyer, Wolfgang Xin, Bo-Tao Weyburne, Emily S. Huber, Eva M. Driessen, Christoph Janssens, Marissa van der Marel, Gijsbert A. Florea, Bogdan I. Maurits, Elmer Overkleeft, Herman S. Espinal, Christofer Du, Yimeng Kisselev, Alexei F. Groll, Michael de Bruin, Gerjan |
| Author_xml | – sequence: 1 givenname: Bo-Tao surname: Xin fullname: Xin, Bo-Tao organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 2 givenname: Eva M. surname: Huber fullname: Huber, Eva M. organization: Tech Univ Munich, Lehrstuhl Biochem, Dept Chem, Ctr Integrated Prot Sci, D-85748 Garching, Germany – sequence: 3 givenname: Gerjan surname: de Bruin fullname: de Bruin, Gerjan organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 4 givenname: Wolfgang surname: Heinemeyer fullname: Heinemeyer, Wolfgang organization: Tech Univ Munich, Lehrstuhl Biochem, Dept Chem, Ctr Integrated Prot Sci, D-85748 Garching, Germany – sequence: 5 givenname: Elmer surname: Maurits fullname: Maurits, Elmer organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 6 givenname: Christofer surname: Espinal fullname: Espinal, Christofer organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 7 givenname: Yimeng surname: Du fullname: Du, Yimeng organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 8 givenname: Marissa surname: Janssens fullname: Janssens, Marissa organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 9 givenname: Emily S. surname: Weyburne fullname: Weyburne, Emily S. organization: Geisel Sch Med Dartmouth, Dept Mol & Syst Biol, 1 Med Ctr Dr HB7936, Lebanon, NH 03756 USA – sequence: 10 givenname: Alexei F. surname: Kisselev fullname: Kisselev, Alexei F. organization: Geisel Sch Med Dartmouth, Dept Mol & Syst Biol, 1 Med Ctr Dr HB7936, Lebanon, NH 03756 USA – sequence: 11 givenname: Bogdan I. surname: Florea fullname: Florea, Bogdan I. organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 12 givenname: Christoph surname: Driessen fullname: Driessen, Christoph organization: Kantonsspital St Gallen, Dept Hematol & Oncol, CH-9007 St Gallen, Switzerland – sequence: 13 givenname: Gijsbert A. surname: van der Marel fullname: van der Marel, Gijsbert A. organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands – sequence: 14 givenname: Michael orcidid: 0000-0002-1660-340X surname: Groll fullname: Groll, Michael email: michael.groll@tum.de organization: Tech Univ Munich, Lehrstuhl Biochem, Dept Chem, Ctr Integrated Prot Sci, D-85748 Garching, Germany – sequence: 15 givenname: Herman S. orcidid: 0000-0001-6976-7005 surname: Overkleeft fullname: Overkleeft, Herman S. email: h.s.overkleeft@chem.leidenuniv.nl organization: Leiden Inst Chem, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands |
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| Keywords | YEAST MECHANISM CRYSTAL-STRUCTURE IMMUNOPROTEASOME SUBSTRATE KNOWLEDGE SITES GENERATION BORTEZOMIB 20S PROTEASOMES |
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| Title | Structure-Based Design of Inhibitors Selective for Human Proteasome beta 2c or beta 2i Subunits |
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