Figure 1.
Figure 1. Heparin catalysis of thrombin inhibition by
antithrombin. (a) The binding of the specific heparin
pentasaccharide to antithrombin induces a global conformational
change involving the expulsion of the hinge region (circled) of
the reactive center loop (RCL, yellow) from the central -sheet
A (red), and extension (yellow) of the A and D helices (green
and cyan, respectively). The expulsion of the hinge region
increases the flexibility of the RCL and liberates the P1 Arg
(green ball-and-stick). The flexibility of the C-terminal
portion of the RCL (P' side) is limited, despite a three-residue
insertion (orange), owing to a tight hydrogen-bonded turn. (b)
Stereo representation of the crystal structure of the ternary
complex between antithrombin (colored as above), thrombin
(magenta) and heparin (ball-and-stick, with blue 2F[o] - F[c]
electron density contoured at 1 ).
Thrombin is docked toward the heparin-binding site of
antithrombin, and makes several exosite interactions. The
expulsion of the hinge region is not required to form this
complex, but the P' side of the RCL (orange) has been elongated.
(c) Density (calculated as in b) of the hinge region of
antithrombin in its complex with thrombin and heparin (yellow)
reveals the insertion of P15 Gly into -sheet
A, and a larger opening between strands 3 and 5A than seen for
pentasaccharide-bound antithrombin alone (gray). It has been
shown that high-affinity binding is not inconsistent with a
native-like hinge conformation, as demonstrated by the structure
in PDB entry 1NQ9 (ref. 42) (brown). (d) A comparison of the
conformations of the P' region of the RCL of pentasaccharide
activated antithrombin (gray) to that of antithrombin in the
complex with thrombin and heparin (yellow, oriented as in a and
b) reveals the requirement for P' elongation through the
breaking of hydrogen bonds.
The above figure is reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2004,
11,
857-862)
copyright 2004.
-sheet
A (red), and extension (yellow) of the A and D helices (green
and cyan, respectively). The expulsion of the hinge region
increases the flexibility of the RCL and liberates the P1 Arg
(green ball-and-stick). The flexibility of the C-terminal
portion of the RCL (P' side) is limited, despite a three-residue
insertion (orange), owing to a tight hydrogen-bonded turn. (b)
Stereo representation of the crystal structure of the ternary
complex between antithrombin (colored as above), thrombin
(magenta) and heparin (ball-and-stick, with blue 2F[o] - F[c]
electron density contoured at 1 
).
Thrombin is docked toward the heparin-binding site of
antithrombin, and makes several exosite interactions. The
expulsion of the hinge region is not required to form this
complex, but the P' side of the RCL (orange) has been elongated.
(c) Density (calculated as in b) of the hinge region of
antithrombin in its complex with thrombin and heparin (yellow)
reveals the insertion of P15 Gly into