Fluorine in PDB 6jt3: Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide

Enzymatic activity of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide

All present enzymatic activity of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide:
3.4.23.46;

Protein crystallography data

The structure of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide, PDB code: 6jt3 was solved by G.Tadano, K.Komano, S.Yoshida, S.Suzuki, K.Nakahara, K.Fuchino, K.Fujimoto, E.Matsuoka, T.Yamamoto, N.Asada, H.Ito, G.Sakaguchi, N.Kanegawa, Y.Kido, S.Ando, T.Fukushima, A.Teisman, V.Urmaliya, D.Dhuyvetter, H.Borghys, A.V.D.Bergh, N.Austin, H.J.M.Gijsen, Y.Yamano, Y.Iso, K.I.Kusakabe, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 20.00 / 2.40
Space group P 61 2 2
Cell size a, b, c (Å), α, β, γ (°) 101.210, 101.210, 171.351, 90.00, 90.00, 120.00
R / Rfree (%) 18.7 / 24.3

Other elements in 6jt3:

The structure of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide also contains other interesting chemical elements:

Iodine (I) 2 atoms

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide (pdb code 6jt3). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 3 binding sites of Fluorine where determined in the Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide, PDB code: 6jt3:
Jump to Fluorine binding site number: 1; 2; 3;

Fluorine binding site 1 out of 3 in 6jt3

Go back to Fluorine Binding Sites List in 6jt3
Fluorine binding site 1 out of 3 in the Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F505

b:29.2
occ:1.00
F2 A:C83505 0.0 29.2 1.0
C17 A:C83505 1.4 27.3 1.0
C1 A:C83505 2.3 27.6 1.0
C15 A:C83505 2.4 26.9 1.0
C A:C83505 2.8 26.7 1.0
N3 A:C83505 2.8 27.4 1.0
C16 A:C83505 2.9 25.9 1.0
S A:C83505 3.0 26.9 1.0
C14 A:C83505 3.1 27.5 1.0
CE1 A:TYR71 3.2 38.3 1.0
C1 A:DMS504 3.2 72.3 1.0
O A:DMS504 3.4 71.9 1.0
CD1 A:TYR71 3.5 40.4 1.0
C2 A:C83505 3.7 28.0 1.0
S A:DMS504 3.8 74.8 1.0
CZ A:TYR71 4.0 38.5 1.0
N4 A:C83505 4.1 27.1 1.0
F1 A:C83505 4.1 30.0 1.0
C13 A:C83505 4.4 28.2 1.0
OH A:TYR71 4.4 40.0 1.0
CG A:TYR71 4.5 40.9 1.0
C3 A:C83505 4.7 27.0 1.0
O A:GLY34 4.8 26.8 1.0
CB A:SER35 4.8 23.4 1.0
OD2 A:ASP32 4.9 20.4 1.0
CE2 A:TYR71 4.9 39.1 1.0

Fluorine binding site 2 out of 3 in 6jt3

Go back to Fluorine Binding Sites List in 6jt3
Fluorine binding site 2 out of 3 in the Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F505

b:30.0
occ:1.00
F1 A:C83505 0.0 30.0 1.0
C13 A:C83505 1.3 28.2 1.0
C12 A:C83505 2.4 27.8 1.0
C2 A:C83505 2.5 28.0 1.0
C1 A:C83505 3.0 27.6 1.0
C A:C83505 3.0 26.7 1.0
C17 A:C83505 3.1 27.3 1.0
CE1 A:PHE108 3.2 28.3 1.0
CE2 A:TYR71 3.2 39.1 1.0
CZ A:TYR71 3.3 38.5 1.0
CD1 A:PHE108 3.3 29.0 1.0
OH A:TYR71 3.5 40.0 1.0
C11 A:C83505 3.6 27.4 1.0
C3 A:C83505 3.7 27.0 1.0
CD2 A:TYR71 3.9 40.5 1.0
CD1 A:ILE118 3.9 29.3 1.0
O A:HOH786 3.9 42.2 1.0
CE1 A:TYR71 4.0 38.3 1.0
C15 A:C83505 4.1 26.9 1.0
F2 A:C83505 4.1 29.2 1.0
C4 A:C83505 4.1 27.1 1.0
N3 A:C83505 4.4 27.4 1.0
CZ A:PHE108 4.5 28.2 1.0
CG A:TYR71 4.5 40.9 1.0
CD1 A:TYR71 4.5 40.4 1.0
CG A:PHE108 4.7 28.9 1.0
C16 A:C83505 4.9 25.9 1.0

Fluorine binding site 3 out of 3 in 6jt3

Go back to Fluorine Binding Sites List in 6jt3
Fluorine binding site 3 out of 3 in the Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of Crystal Structure of BACE1 in Complex with N-{3-[(4R,5R,6R)-2-Amino-5- Fluoro-4,6-Dimethyl-5,6-Dihydro-4H-1,3-Thiazin-4-Yl]-4-Fluorophenyl}- 5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F505

b:30.3
occ:1.00
F A:C83505 0.0 30.3 1.0
C9 A:C83505 1.4 29.8 1.0
O A:C83505 2.3 28.6 1.0
C8 A:C83505 2.9 28.2 1.0
N2 A:C83505 3.0 27.8 1.0
N A:GLY13 3.0 29.7 1.0
CA A:GLY13 3.3 28.2 1.0
N A:GLY11 3.6 38.1 1.0
N A:GLN12 3.8 33.0 1.0
CE2 A:TYR14 3.8 26.5 1.0
CA A:GLY11 3.8 35.4 1.0
C A:GLY11 3.9 34.6 1.0
C7 A:C83505 4.1 27.1 1.0
C A:GLY13 4.1 27.6 1.0
CD2 A:TYR14 4.2 26.4 1.0
C A:GLN12 4.2 30.4 1.0
C10 A:C83505 4.2 26.9 1.0
O A:LYS9 4.3 41.7 1.0
O A:GLY13 4.5 28.0 1.0
NH2 A:ARG307 4.5 27.1 0.5
OG1 A:THR232 4.5 27.8 1.0
CA A:GLN12 4.6 30.8 1.0
C A:SER10 4.6 39.1 1.0
CZ A:TYR14 4.6 26.7 1.0
CB A:ALA335 4.7 27.0 1.0
OE1 A:GLU339 4.7 34.6 1.0
O A:GLY11 4.8 33.4 1.0
OH A:TYR14 4.9 27.4 1.0
N A:TYR14 5.0 26.8 1.0
CA A:SER10 5.0 40.9 1.0

Reference:

G.Tadano, K.Komano, S.Yoshida, S.Suzuki, K.Nakahara, K.Fuchino, K.Fujimoto, E.Matsuoka, T.Yamamoto, N.Asada, H.Ito, G.Sakaguchi, N.Kanegawa, Y.Kido, S.Ando, T.Fukushima, A.Teisman, V.Urmaliya, D.Dhuyvetter, H.Borghys, A.Van Den Bergh, N.Austin, H.J.M.Gijsen, Y.Yamano, Y.Iso, K.I.Kusakabe. Discovery of An Extremely Potent Thiazine-Based Beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at A Low Projected Human Dose. J.Med.Chem. V. 62 9331 2019.
ISSN: ISSN 0022-2623
PubMed: 31549838
DOI: 10.1021/ACS.JMEDCHEM.9B01140
Page generated: Sun Dec 13 12:54:41 2020

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