The effect of these mutations was firstly to render the protein more stable in detergents used for crystallization and secondly to push the conformational equilibrium of the protein towards the antagonist bound state.
Germline adenomatous polyposis coli (APC) mutations were firstly described in 1991 1, 2 as causing FAP with an autosomal dominant pattern of inheritance.
Complementary, EGFR mutations were firstly reported in lung cancer patients who had greater response to treatment with EGFR tyrosine kinase inhibitors.
BRCA1 mutations were firstly divided by position relative to amino acid 1365 (nucleotide 4213), because mutations 5' of this have been reported to exhibit markedly decreased AR transactivation ability [ 11].
Further through protein structure analysis and site-directed mutation in CrGES, it was firstly demonstrated that among the high-conserved amino acid residues located in active pocket, Y436 and D501 with strong affinity to diphosphate function group, were critical for the dephosphorylation (the core step for geraniol formation).
We further analysed mutation patterns when drug resistance was firstly detected in a given year of treatment.
Loss or mutation of the BRCA1 gene was firstly described to be associated with increased risk of breast and ovarian cancers [ 80, 82– 86].
The higher sensitivity to detect the JAK2V617F mutation at the RNA level was firstly demonstrated by the above mentioned study of Vannucchi et al. [ 11], who reported an increased percentage (9 %) of JAK2-mutated ET patients by using RNA instead of DNA.
Intermediate vector pC3.1 was firstly constructed through mutation of pcDNA 3.1 with primer set 5′CTCGGTCGTTCGGCTGCG3′ and 5′GGCGCGTGGGGATACCC3′, by which the SV40 origin and neomycin selection gene region was deleted.
The S81L pathogenic mutation has been firstly identified by Williams et al. (19).
