Hotspots in an obligate homodimeric anticancer target: structural and functional effects of interfacial mutations in human thymidylate synthase
Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 23, 2015
|
| In: |
Journal of medicinal chemistry
Year: 2015, Volume: 58, Issue: 8, Pages: 3572-3581 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.5b00137 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.5b00137
|
| Author Notes: | Outi M.H. Salo-Ahen, Anna Tochowicz, Cecilia Pozzi, Daniela Cardinale, Stefania Ferrari, Yap Boum, Stefano Mangani, Robert M. Stroud, Puneet Saxena, Hannu Myllykallio, Maria Paola Costi, Glauco Ponterini, and Rebecca C. Wade |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1724101455 | ||
| 003 | DE-627 | ||
| 005 | 20230426081755.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200709s2015 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.5b00137 |2 doi | |
| 035 | |a (DE-627)1724101455 | ||
| 035 | |a (DE-599)KXP1724101455 | ||
| 035 | |a (OCoLC)1341345085 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 32 |2 sdnb | ||
| 100 | 1 | |a Salo-Ahen, Outi M. H. |e VerfasserIn |0 (DE-588)1188069403 |0 (DE-627)1666994952 |4 aut | |
| 245 | 1 | 0 | |a Hotspots in an obligate homodimeric anticancer target |b structural and functional effects of interfacial mutations in human thymidylate synthase |c Outi M.H. Salo-Ahen, Anna Tochowicz, Cecilia Pozzi, Daniela Cardinale, Stefania Ferrari, Yap Boum, Stefano Mangani, Robert M. Stroud, Puneet Saxena, Hannu Myllykallio, Maria Paola Costi, Glauco Ponterini, and Rebecca C. Wade |
| 264 | 1 | |c March 23, 2015 | |
| 300 | |b Illustrationen | ||
| 300 | |a 10 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 09.07.2020 | ||
| 520 | |a Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild-type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate KM values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface. | ||
| 700 | 1 | |a Tochowicz, Anna |e VerfasserIn |4 aut | |
| 700 | 1 | |a Pozzi, Cecilia |e VerfasserIn |4 aut | |
| 700 | 1 | |a Cardinale, Daniela |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ferrari, Stefania |e VerfasserIn |4 aut | |
| 700 | 1 | |a Boum, Yap |e VerfasserIn |4 aut | |
| 700 | 1 | |a Mangani, Stefano |e VerfasserIn |4 aut | |
| 700 | 1 | |a Stroud, Robert M. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Saxena, Puneet |e VerfasserIn |4 aut | |
| 700 | 1 | |a Myllykallio, Hannu |e VerfasserIn |4 aut | |
| 700 | 1 | |a Costi, Maria Paola |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ponterini, Glauco |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wade, Rebecca C. |e VerfasserIn |0 (DE-588)102801774X |0 (DE-627)730136000 |0 (DE-576)276591402 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d Washington, DC : ACS, 1959 |g 58(2015), 8, Seite 3572-3581 |h Online-Ressource |w (DE-627)302468846 |w (DE-600)1491411-6 |w (DE-576)090855132 |x 1520-4804 |7 nnas |a Hotspots in an obligate homodimeric anticancer target structural and functional effects of interfacial mutations in human thymidylate synthase |
| 773 | 1 | 8 | |g volume:58 |g year:2015 |g number:8 |g pages:3572-3581 |g extent:10 |a Hotspots in an obligate homodimeric anticancer target structural and functional effects of interfacial mutations in human thymidylate synthase |
| 856 | 4 | 0 | |u https://doi.org/10.1021/acs.jmedchem.5b00137 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20200709 | ||
| 993 | |a Article | ||
| 994 | |a 2015 | ||
| 998 | |g 102801774X |a Wade, Rebecca C. |m 102801774X:Wade, Rebecca C. |d 140000 |e 140000PW102801774X |k 0/140000/ |p 13 |y j | ||
| 999 | |a KXP-PPN1724101455 |e 3722670411 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"part":{"text":"58(2015), 8, Seite 3572-3581","extent":"10","pages":"3572-3581","volume":"58","issue":"8","year":"2015"},"id":{"issn":["1520-4804"],"zdb":["1491411-6"],"eki":["302468846"]},"origin":[{"publisherPlace":"Washington, DC ; Easton, Pa.","dateIssuedKey":"1959","publisher":"ACS ; ACS","dateIssuedDisp":"1959-"}],"disp":"Hotspots in an obligate homodimeric anticancer target structural and functional effects of interfacial mutations in human thymidylate synthaseJournal of medicinal chemistry","name":{"displayForm":["American Chemical Society"]},"recId":"302468846","title":[{"title":"Journal of medicinal chemistry","title_sort":"Journal of medicinal chemistry"}],"pubHistory":["1.1959 -"],"language":["eng"],"physDesc":[{"extent":"Online-Ressource"}],"type":{"media":"Online-Ressource","bibl":"periodical"},"note":["Gesehen am 02.10.2020"]}],"note":["Gesehen am 09.07.2020"],"origin":[{"dateIssuedDisp":"March 23, 2015","dateIssuedKey":"2015"}],"id":{"doi":["10.1021/acs.jmedchem.5b00137"],"eki":["1724101455"]},"recId":"1724101455","name":{"displayForm":["Outi M.H. Salo-Ahen, Anna Tochowicz, Cecilia Pozzi, Daniela Cardinale, Stefania Ferrari, Yap Boum, Stefano Mangani, Robert M. Stroud, Puneet Saxena, Hannu Myllykallio, Maria Paola Costi, Glauco Ponterini, and Rebecca C. Wade"]},"title":[{"subtitle":"structural and functional effects of interfacial mutations in human thymidylate synthase","title":"Hotspots in an obligate homodimeric anticancer target","title_sort":"Hotspots in an obligate homodimeric anticancer target"}],"person":[{"display":"Salo-Ahen, Outi M. H.","given":"Outi M. H.","role":"aut","family":"Salo-Ahen"},{"family":"Tochowicz","role":"aut","given":"Anna","display":"Tochowicz, Anna"},{"display":"Pozzi, Cecilia","family":"Pozzi","given":"Cecilia","role":"aut"},{"display":"Cardinale, Daniela","family":"Cardinale","given":"Daniela","role":"aut"},{"display":"Ferrari, Stefania","role":"aut","given":"Stefania","family":"Ferrari"},{"display":"Boum, Yap","family":"Boum","role":"aut","given":"Yap"},{"display":"Mangani, Stefano","family":"Mangani","role":"aut","given":"Stefano"},{"display":"Stroud, Robert M.","family":"Stroud","given":"Robert M.","role":"aut"},{"family":"Saxena","given":"Puneet","role":"aut","display":"Saxena, Puneet"},{"family":"Myllykallio","role":"aut","given":"Hannu","display":"Myllykallio, Hannu"},{"family":"Costi","given":"Maria Paola","role":"aut","display":"Costi, Maria Paola"},{"display":"Ponterini, Glauco","given":"Glauco","role":"aut","family":"Ponterini"},{"given":"Rebecca C.","role":"aut","family":"Wade","display":"Wade, Rebecca C."}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"physDesc":[{"extent":"10 S.","noteIll":"Illustrationen"}],"language":["eng"]} | ||
| SRT | |a SALOAHENOUHOTSPOTSIN2320 | ||