Matches in SemOpenAlex for { <https://semopenalex.org/work/W1827782944> ?p ?o ?g. }
- W1827782944 endingPage "14652" @default.
- W1827782944 startingPage "14640" @default.
- W1827782944 abstract "We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X···S halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cε of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%)." @default.
- W1827782944 created "2016-06-24" @default.
- W1827782944 creator A5001635855 @default.
- W1827782944 creator A5002907072 @default.
- W1827782944 creator A5007510357 @default.
- W1827782944 creator A5020943735 @default.
- W1827782944 creator A5027617437 @default.
- W1827782944 creator A5029265500 @default.
- W1827782944 creator A5031324853 @default.
- W1827782944 creator A5037137796 @default.
- W1827782944 creator A5054574030 @default.
- W1827782944 creator A5061646495 @default.
- W1827782944 creator A5073433096 @default.
- W1827782944 creator A5075394155 @default.
- W1827782944 creator A5080662411 @default.
- W1827782944 creator A5086525697 @default.
- W1827782944 creator A5089105659 @default.
- W1827782944 date "2015-11-12" @default.
- W1827782944 modified "2023-10-16" @default.
- W1827782944 title "Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond" @default.
- W1827782944 cites W1891159913 @default.
- W1827782944 cites W1903376799 @default.
- W1827782944 cites W1964004579 @default.
- W1827782944 cites W1981753260 @default.
- W1827782944 cites W1982346259 @default.
- W1827782944 cites W1993289010 @default.
- W1827782944 cites W1993311612 @default.
- W1827782944 cites W2001008758 @default.
- W1827782944 cites W2016373164 @default.
- W1827782944 cites W2018398804 @default.
- W1827782944 cites W2019452934 @default.
- W1827782944 cites W2027392184 @default.
- W1827782944 cites W2030205108 @default.
- W1827782944 cites W2030579248 @default.
- W1827782944 cites W2034934393 @default.
- W1827782944 cites W2043156888 @default.
- W1827782944 cites W2047710091 @default.
- W1827782944 cites W2051664811 @default.
- W1827782944 cites W2054975178 @default.
- W1827782944 cites W2075203410 @default.
- W1827782944 cites W2080130231 @default.
- W1827782944 cites W2083752746 @default.
- W1827782944 cites W2084474185 @default.
- W1827782944 cites W2085299200 @default.
- W1827782944 cites W2094742663 @default.
- W1827782944 cites W2095453782 @default.
- W1827782944 cites W2103381809 @default.
- W1827782944 cites W2107803606 @default.
- W1827782944 cites W2114869204 @default.
- W1827782944 cites W2119913705 @default.
- W1827782944 cites W2130437495 @default.
- W1827782944 cites W2159356452 @default.
- W1827782944 cites W2161205137 @default.
- W1827782944 cites W2166344128 @default.
- W1827782944 cites W2169825456 @default.
- W1827782944 cites W2314431251 @default.
- W1827782944 cites W2317325743 @default.
- W1827782944 cites W2333083696 @default.
- W1827782944 cites W2335462654 @default.
- W1827782944 cites W636297489 @default.
- W1827782944 doi "https://doi.org/10.1021/jacs.5b07090" @default.
- W1827782944 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26505827" @default.
- W1827782944 hasPublicationYear "2015" @default.
- W1827782944 type Work @default.
- W1827782944 sameAs 1827782944 @default.
- W1827782944 citedByCount "67" @default.
- W1827782944 countsByYear W18277829442016 @default.
- W1827782944 countsByYear W18277829442017 @default.
- W1827782944 countsByYear W18277829442018 @default.
- W1827782944 countsByYear W18277829442019 @default.
- W1827782944 countsByYear W18277829442020 @default.
- W1827782944 countsByYear W18277829442021 @default.
- W1827782944 countsByYear W18277829442022 @default.
- W1827782944 countsByYear W18277829442023 @default.
- W1827782944 crossrefType "journal-article" @default.
- W1827782944 hasAuthorship W1827782944A5001635855 @default.
- W1827782944 hasAuthorship W1827782944A5002907072 @default.
- W1827782944 hasAuthorship W1827782944A5007510357 @default.
- W1827782944 hasAuthorship W1827782944A5020943735 @default.
- W1827782944 hasAuthorship W1827782944A5027617437 @default.
- W1827782944 hasAuthorship W1827782944A5029265500 @default.
- W1827782944 hasAuthorship W1827782944A5031324853 @default.
- W1827782944 hasAuthorship W1827782944A5037137796 @default.
- W1827782944 hasAuthorship W1827782944A5054574030 @default.
- W1827782944 hasAuthorship W1827782944A5061646495 @default.
- W1827782944 hasAuthorship W1827782944A5073433096 @default.
- W1827782944 hasAuthorship W1827782944A5075394155 @default.
- W1827782944 hasAuthorship W1827782944A5080662411 @default.
- W1827782944 hasAuthorship W1827782944A5086525697 @default.
- W1827782944 hasAuthorship W1827782944A5089105659 @default.
- W1827782944 hasConcept C118792377 @default.
- W1827782944 hasConcept C158733187 @default.
- W1827782944 hasConcept C161790260 @default.
- W1827782944 hasConcept C178790620 @default.
- W1827782944 hasConcept C184235292 @default.
- W1827782944 hasConcept C185592680 @default.
- W1827782944 hasConcept C21951064 @default.
- W1827782944 hasConcept C23029723 @default.