NucleaRDB: Extraction of mutation data from the literature

This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes the selected point mutation and provides links to other documents. The sentence(s) where the point mutation W443Y was found are listed after the table.

The mutated residues are also indicated in the family sequence alignments and hyperlinked to the corresponding mutation pages.

Point mutation W443Y in NR1H3_HUMAN

Relevant sentences:

W443

• The side-chain rotamers of W443 and I295 were manually adjusted to accommodate GW3965 , without disrupting the overall protein fold

• The sense strand oligonucleotide sequences are as follows: F254A GGCCCGTCAGCAGCGCGCTGCCCACTTCACTGAGC F257A GCAGCGCTTTGCCCACGCCACTGAGCTGGCCATC M298A GACCTCTGCGATCGAGGTGGCGCTTCTGGAGACATCTCG L299A GCGATCGAGGTGATGGCTCTGGAGACATCTCGGAGG E301A CGAGGTGATGCTTCTGGCGACATCTCGGAGGTACAACC T302A GCTTCTGGAGGCATCTCGGAGGTACAACC R305L GCTTCTGGAGACATCTCGGCTGTACAACCCTGGG F315A CACTTCCTCAAGGATGCCAGTTATAACCGGGAAG L316A GGAGTGAGAGTATCACCTTCGCCAAGGATTTCAGTTATAACCGGG L331A GGAAGACTTTGCCAAAGCAGGGGCGCAAGTGGAATTCATCAA F335A GCAGGGCTGCAAGTGGAAGCCATCAACCCCATCTTCG H421A GGACCCTGAGCAGCGTCGCCTCAGAGCAAGTGTTTGC Q424A GCAGCGTCCACTCAGAGGCAGTGTTTGCACTGCGTCTGC L439A GCTCCCACCGCTGGCCTCTGAGATCTGGGATGTGC I442A GCTGCACATCCCAGGCCTCAGAGAGCAGCGGTGGG W443Y CACCGCTGCTCTCTGAGATCTACGATGTGCACGAATG Mutagenesis was confirmed by sequence analysis

• Spencer et al. could not explain the activity of 20(S)-hydroxycholesterol (20SHC) by the pharmacophore hypothesis in which the hydroxyl / or epoxide of the oxysterols forming a hydrogen bond with W443

• These two pockets are boarded by W443 and H421

• Mutations W443Y , L299A and L316A revealed ligand-specific interaction of these residues in the transcriptional assay

• In agreement with Spencer et al. [20 ] we observed complete loss of transcriptional activation by 22RHC in the presence of a W443Y substitution

• W443 has been proposed to serve as a hydrogen bond donor to the hydroxyl or carbonyl groups on C17 side chain the oxysterols ; however , the conclusion is not exclusive since the hydroxyl group of tyrosine could also act as a hydrogen bond donor

• Accordingly , we suggest an orientation whereby W443 participates in a hydrophobic interaction with 22RHC

• Indeed , the loss of transcriptional induction by W443Y in the presence of 22RHC and T0901317 likely results from a van der Waals collision when W443 is replaced with tyrosine

• Mutation of W443Y did not result in as dramatic of a reduction in transcription in the presence of GW3965

• Based on our docking model , we propose an edge-to-face interaction between the A ring of GW3965 with W443 and F257 of the LBD ( Fig. 3D ) ; hence , the slight difference in GW3965-mediated transactivation between the W443Y mutant and the wild-type LBD may be caused by the redistribution of small pi , Greek-electron clouds on the aromatic ring

W443Y

• The sense strand oligonucleotide sequences are as follows: F254A GGCCCGTCAGCAGCGCGCTGCCCACTTCACTGAGC F257A GCAGCGCTTTGCCCACGCCACTGAGCTGGCCATC M298A GACCTCTGCGATCGAGGTGGCGCTTCTGGAGACATCTCG L299A GCGATCGAGGTGATGGCTCTGGAGACATCTCGGAGG E301A CGAGGTGATGCTTCTGGCGACATCTCGGAGGTACAACC T302A GCTTCTGGAGGCATCTCGGAGGTACAACC R305L GCTTCTGGAGACATCTCGGCTGTACAACCCTGGG F315A CACTTCCTCAAGGATGCCAGTTATAACCGGGAAG L316A GGAGTGAGAGTATCACCTTCGCCAAGGATTTCAGTTATAACCGGG L331A GGAAGACTTTGCCAAAGCAGGGGCGCAAGTGGAATTCATCAA F335A GCAGGGCTGCAAGTGGAAGCCATCAACCCCATCTTCG H421A GGACCCTGAGCAGCGTCGCCTCAGAGCAAGTGTTTGC Q424A GCAGCGTCCACTCAGAGGCAGTGTTTGCACTGCGTCTGC L439A GCTCCCACCGCTGGCCTCTGAGATCTGGGATGTGC I442A GCTGCACATCCCAGGCCTCAGAGAGCAGCGGTGGG W443Y CACCGCTGCTCTCTGAGATCTACGATGTGCACGAATG Mutagenesis was confirmed by sequence analysis

• Mutations W443Y , L299A and L316A revealed ligand-specific interaction of these residues in the transcriptional assay

• In agreement with Spencer et al. [20 ] we observed complete loss of transcriptional activation by 22RHC in the presence of a W443Y substitution

• Indeed , the loss of transcriptional induction by W443Y in the presence of 22RHC and T0901317 likely results from a van der Waals collision when W443 is replaced with tyrosine

• Mutation of W443Y did not result in as dramatic of a reduction in transcription in the presence of GW3965

• Based on our docking model , we propose an edge-to-face interaction between the A ring of GW3965 with W443 and F257 of the LBD ( Fig. 3D ) ; hence , the slight difference in GW3965-mediated transactivation between the W443Y mutant and the wild-type LBD may be caused by the redistribution of small pi , Greek-electron clouds on the aromatic ring

F.Horn (nucleardbcmbi.kun.nl), 21-Apr-2005