2OD3

Human thrombin chimera with human residues 184a, 186, 186a, 186b, 186c and 222 replaced by murine thrombin equivalents.

Summary for 2OD3

• Entry DOI: 10.2210/pdb2od3/pdb
• Related: 1SHH
• Related PRD ID: PRD_000020
• Descriptor: Thrombin light chain, Thrombin heavy chain, D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide, ... (5 entities in total)
• Functional Keywords: serine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 34581.09

Authors

Marino, F.,Chen, Z.,Ergenekan, C.E.,Bush, L.A.,Mathews, F.S.,Di Cera, E. (deposition date: 2006-12-21, release date: 2007-04-10, Last modification date: 2024-10-16)

Primary citation

Marino, F.,Chen, Z.W.,Ergenekan, C.E.,Bush-Pelc, L.A.,Mathews, F.S.,Di Cera, E.
Structural basis of na+ activation mimicry in murine thrombin.
J.Biol.Chem., 282:16355-16361, 2007

PubMed Abstract: Unlike human thrombin, murine thrombin lacks Na+ activation due to the charge reversal substitution D222K in the Na+ binding loop. However, the enzyme is functionally stabilized in a Na+-bound form and is highly active toward physiologic substrates. The structural basis of this peculiar property is unknown. Here, we present the 2.2 A resolution x-ray crystal structure of murine thrombin in the absence of inhibitors and salts. The enzyme assumes an active conformation, with Ser-195, Glu-192, and Asp-189 oriented as in the Na+-bound fast form of human thrombin. Lys-222 completely occludes the pore of entry to the Na+ binding site and positions its side chain inside the pore, with the Nzeta atom H-bonded to the backbone oxygen atoms of Lys-185, Asp-186b, and Lys-186d. The same architecture is observed in the 1.75 A resolution structure of a thrombin chimera in which the human enzyme carries all residues defining the Na+ pore in the murine enzyme. These findings demonstrate that Na+ activation in thrombin is linked to the architecture of the Na+ pore. The molecular strategy of Na+ activation mimicry unraveled for murine thrombin is relevant to serine proteases and enzymes activated by monovalent cations in general.

PubMed: 17428793
DOI: 10.1074/jbc.M701323200

Experimental method

X-RAY DIFFRACTION (1.75 Å)