Table 4.
In silico analysis of CYP2C9 (PDB ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=1OG2, UniProt: http://www.uniprot.org/uniprot/P11712; GenBank: KF248057.1)
|
CYP2C9 Amino acid/mutation/alleles |
DUET ΔΔG, kcal/mol |
PopMusica ΔΔG, kcal/mol |
SAAFEC ΔΔG, kcal/mol |
MAESTROwebb ΔΔG, kcal/mol |
PolyPhen‐2 Score/mutation prediction |
MSAc aa conservation |
Involved in predicted ligand‐binding pockets/pocket No. (FTMap) | Involved in known or predicted channels | Involved in predicted PPI sites (meta‐PPISP) | Node degree (RING‐2.0) | Predicted fluctuation value (FlexPred) | Flexibility classd (PredyFlexy) | Decreased metabolic activity or protein expression | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Arg132 R132Q CYP2C9*33 |
−0.136 Destabilizing |
0.33 Destabilizing SA = 54.9% |
−2.112 Destabilizing |
1.126 Destabilizing Cpred = 0.756 |
0.973 Probably damaging |
High | No | No | Yes | 8 | 1.563 | 1 | Decreased catalytic activity enzyme toward losartan (in vitro) | Yin et al. (2008) |
|
Arg150 R150H CYP2C9*8 |
−0.55 Destabilizing |
0.15 Destabilizing SA = 60.4% |
−5.940 Destabilizing |
0.380 Destabilizing Cpred = 0.793 |
0.071 Benign |
High | No | No | No | 8 | 1.359 | 0 | Decrease in enzyme activity (in vitro and in vivo) | Allabi et al. (2005) |
|
Ile359 I359L CYP2C9*3 |
−0.457 Destabilizing |
−0.41 Stabilizing SA = 1.4% |
−1.763 Destabilizing |
−0.395 Stabilizing Cpred = 0.892 |
0.002 Benign |
High | No | No | No | 9 | 1.144 | 1 | Decreased enzymatic activity (in vitro and in vivo) |
Shintani et al. (2001) King et al. (2004) |
|
Ile434 I434F CYP2C9*59 |
−0.97 Destabilizing |
0.70 Destabilizing SA = 22.1% |
−0.385 Destabilizing |
0.014 Destabilizing Cpred = 0.955 |
0.969 Probably damaging |
High | Yes/1 and 5 | No | Yes | 6 | 1.033 | 1 | Greatly decreased enzymatic activity (in vitro and in vivo) | Dai et al. (2015) |
For the program PopMusic solvent accessibility (SA) values are shown (in percent).
For the program MaestroWeb the confidence estimation Cpred is shown (0.0‐not reliable and 1.0‐highly reliable).
MSA‐Multiple sequence alignment.
Flexibility class was determined by the program PredyFlexy (rigid‐0, intermediate‐1, flexible‐2).
Wild‐type residue (bold) and amino acid substitution (Underlined).