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Fluorine in PDB 5hg9: Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One

Enzymatic activity of Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One

All present enzymatic activity of Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One:
2.7.10.1;

Protein crystallography data

The structure of Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One, PDB code: 5hg9 was solved by K.S.Gajiwala, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 24.80 / 2.15
Space group P 21 21 21
Cell size a, b, c (Å), α, β, γ (°) 35.205, 69.879, 113.554, 90.00, 90.00, 90.00
R / Rfree (%) 28.7 / 26.3

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One (pdb code 5hg9). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 3 binding sites of Fluorine where determined in the Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One, PDB code: 5hg9:
Jump to Fluorine binding site number: 1; 2; 3;

Fluorine binding site 1 out of 3 in 5hg9

Go back to Fluorine Binding Sites List in 5hg9
Fluorine binding site 1 out of 3 in the Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F9001

b:49.5
occ:1.00
F7 A:63A9001 0.0 49.5 1.0
C6 A:63A9001 1.4 50.0 1.0
F9 A:63A9001 2.2 52.9 1.0
F8 A:63A9001 2.2 51.7 1.0
C5 A:63A9001 2.4 47.8 1.0
C1 A:63A9001 2.9 43.8 1.0
CZ A:PHE723 3.2 39.7 1.0
N A:SER720 3.4 45.3 1.0
C A:GLY719 3.5 44.0 1.0
CE2 A:PHE723 3.7 40.1 1.0
CG2 A:VAL726 3.7 34.5 1.0
C4 A:63A9001 3.8 46.0 1.0
CA A:GLY719 3.8 42.7 1.0
CA A:SER720 4.0 46.4 1.0
CE1 A:PHE856 4.0 33.4 1.0
C2 A:63A9001 4.0 45.1 1.0
C14 A:63A9001 4.0 40.5 1.0
O15 A:63A9001 4.1 30.7 1.0
O A:GLY719 4.1 42.7 1.0
CB A:VAL726 4.2 33.8 1.0
CZ A:PHE856 4.2 31.0 1.0
C A:SER720 4.4 46.7 1.0
CE1 A:PHE723 4.4 39.3 1.0
O A:SER720 4.4 47.6 1.0
N3 A:63A9001 4.5 43.9 1.0
N A:GLY719 4.7 41.8 1.0
CD1 A:PHE856 4.8 33.5 1.0
N A:VAL726 4.8 35.0 1.0
O A:LEU718 4.9 41.5 1.0

Fluorine binding site 2 out of 3 in 5hg9

Go back to Fluorine Binding Sites List in 5hg9
Fluorine binding site 2 out of 3 in the Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F9001

b:51.7
occ:1.00
F8 A:63A9001 0.0 51.7 1.0
C6 A:63A9001 1.4 50.0 1.0
F7 A:63A9001 2.2 49.5 1.0
F9 A:63A9001 2.2 52.9 1.0
C5 A:63A9001 2.4 47.8 1.0
C1 A:63A9001 3.0 43.8 1.0
C4 A:63A9001 3.0 46.0 1.0
C2 A:63A9001 3.1 45.1 1.0
N3 A:63A9001 3.3 43.9 1.0
N A:SER720 3.4 45.3 1.0
CA A:GLY719 3.5 42.7 1.0
C A:GLY719 3.8 44.0 1.0
O A:SER720 4.0 47.6 1.0
O A:LEU718 4.4 41.5 1.0
C10 A:63A9001 4.4 41.7 1.0
CA A:SER720 4.4 46.4 1.0
C14 A:63A9001 4.5 40.5 1.0
C A:SER720 4.5 46.7 1.0
N A:GLY719 4.6 41.8 1.0
O A:GLY719 4.8 42.7 1.0
C A:LEU718 4.9 41.3 1.0

Fluorine binding site 3 out of 3 in 5hg9

Go back to Fluorine Binding Sites List in 5hg9
Fluorine binding site 3 out of 3 in the Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of Egfr (L858R, T790M, V948R) in Complex with 1-[(3R,4R)-3-[({2-[(1- Methyl-1H-Pyrazol-4-Yl)Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-(Trifluoromethyl)Pyrrolidin-1-Yl]Prop-2-En-1-One within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F9001

b:52.9
occ:1.00
F9 A:63A9001 0.0 52.9 1.0
C6 A:63A9001 1.4 50.0 1.0
F7 A:63A9001 2.2 49.5 1.0
F8 A:63A9001 2.2 51.7 1.0
C5 A:63A9001 2.4 47.8 1.0
C4 A:63A9001 3.0 46.0 1.0
CE2 A:PHE723 3.6 40.1 1.0
C1 A:63A9001 3.8 43.8 1.0
CZ A:PHE723 3.9 39.7 1.0
O A:SER720 4.1 47.6 1.0
N3 A:63A9001 4.1 43.9 1.0
CZ A:PHE856 4.2 31.0 1.0
CE1 A:PHE856 4.3 33.4 1.0
C2 A:63A9001 4.4 45.1 1.0
N A:SER720 4.4 45.3 1.0
C A:SER720 4.5 46.7 1.0
CE2 A:PHE856 4.6 33.8 1.0
CD1 A:PHE856 4.7 33.5 1.0
CD2 A:PHE723 4.7 40.3 1.0
CA A:SER720 4.8 46.4 1.0
C14 A:63A9001 4.8 40.5 1.0
CD2 A:PHE856 5.0 34.4 1.0

Reference:

H.Cheng, S.K.Nair, B.W.Murray, C.Almaden, S.Bailey, S.Baxi, D.Behenna, S.Cho-Schultz, D.Dalvie, D.M.Dinh, M.P.Edwards, J.L.Feng, R.A.Ferre, K.S.Gajiwala, M.D.Hemkens, A.Jackson-Fisher, M.Jalaie, T.O.Johnson, R.S.Kania, S.Kephart, J.Lafontaine, B.Lunney, K.K.Liu, Z.Liu, J.Matthews, A.Nagata, S.Niessen, M.A.Ornelas, S.T.Orr, M.Pairish, S.Planken, S.Ren, D.Richter, K.Ryan, N.Sach, H.Shen, T.Smeal, J.Solowiej, S.Sutton, K.Tran, E.Tseng, W.Vernier, M.Walls, S.Wang, S.L.Weinrich, S.Xin, H.Xu, M.J.Yin, M.Zientek, R.Zhou, J.C.Kath. Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-Methyl-1H-Pyrazol-4-Yl) Amino]-7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl}Oxy) Methyl]-4-Methoxypyrrolidin-1-Yl}Prop-2-En-1-One (Pf-06459988), A Potent, Wt Sparing, Irreversible Inhibitor of T790M-Containing Egfr Mutants. J.Med.Chem. V. 59 2005 2016.
ISSN: ISSN 0022-2623
PubMed: 26756222
DOI: 10.1021/ACS.JMEDCHEM.5B01633
Page generated: Sun Dec 13 12:23:36 2020

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