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Crystal Structure of Kunitz Domain 1 of Tissue Factor Pathway Inhibitor-2 with Bovine Trypsin

OverviewOverview

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 inhibits trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor with Ki values of 13, 3, and 1640 nM, respectively. To investigate the molecular specificity of KD1, crystals of the complex of KD1 with bovine beta-trypsin were obtained that diffracted to 1.8 A. The P1 residue Arg-15 (bovine pancreatic trypsin inhibitor numbering) in KD1 interacts with Asp-189 (chymotrypsin numbering) and with the carbonyl oxygens of Gly-219 and Ogamma of Ser-190. Leu-17, Leu-18, Leu-19, and Leu-34 in KD1 make van der Waals contacts with Tyr-39, Phe-41, and Tyr-151 in trypsin, forming a hydrophobic interface. Molecular modeling indicates that this complementary hydrophobic patch is composed of Phe-37, Met-39, and Phe-41 in plasmin, whereas in FVIIa/tissue factor, it is essentially absent. Arg-20, Tyr-46, and Glu-39 in KD1 interact with trypsin through ordered water molecules. In contrast, insertions in the 60-loop in plasmin and FVIIa allow Arg-20 of KD1 to directly interact with Glu-60 in plasmin and Asp-60 in FVIIa. Moreover, Tyr-46 in KD1 electrostatically interacts with Lys-60A and Arg-60D in plasmin and Lys-60A in FVIIa. Glu-39 in KD1 interacts directly with Arg-175 of the basic patch in plasmin, whereas in FVIIa, such interactions are not possible. Thus, the specificity of KD1 for plasmin is attributable to hydrophobic and direct electrostatic interactions. For trypsin, hydrophobic interactions are intact, and electrostatic interactions are weak, whereas for FVIIa, hydrophobic interactions are missing, and electrostatic interactions are partially intact. These findings provide insight into the protease selectivity of KD1.

About this StructureAbout this Structure

1ZR0 is a Protein complex structure of sequences from Bos taurus and Homo sapiens with as ligand. Active as Trypsin, with EC number 3.4.21.4 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 in complex with trypsin. Implications for KD1 specificity of inhibition., Schmidt AE, Chand HS, Cascio D, Kisiel W, Bajaj SP, J Biol Chem. 2005 Jul 29;280(30):27832-8. Epub 2005 Jun 2. PMID:15932872

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 '''Crystal Structure of Kunitz Domain 1 of Tissue Factor Pathway Inhibitor-2 with Bovine Trypsin'''<br />
 ==Overview==
-Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 inhibits, trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor with Ki values of, 13, 3, and 1640 nM, respectively. To investigate the molecular specificity, of KD1, crystals of the complex of KD1 with bovine beta-trypsin were, obtained that diffracted to 1.8 A. The P1 residue Arg-15 (bovine, pancreatic trypsin inhibitor numbering) in KD1 interacts with Asp-189, (chymotrypsin numbering) and with the carbonyl oxygens of Gly-219 and, Ogamma of Ser-190. Leu-17, Leu-18, Leu-19, and Leu-34 in KD1 make van der, Waals contacts with Tyr-39, Phe-41, and Tyr-151 in trypsin, forming a, hydrophobic interface. Molecular modeling indicates that this, complementary hydrophobic patch is composed of Phe-37, Met-39, and Phe-41, in plasmin, whereas in FVIIa/tissue factor, it is essentially absent., Arg-20, Tyr-46, and Glu-39 in KD1 interact with trypsin through ordered, water molecules. In contrast, insertions in the 60-loop in plasmin and, FVIIa allow Arg-20 of KD1 to directly interact with Glu-60 in plasmin and, Asp-60 in FVIIa. Moreover, Tyr-46 in KD1 electrostatically interacts with, Lys-60A and Arg-60D in plasmin and Lys-60A in FVIIa. Glu-39 in KD1, interacts directly with Arg-175 of the basic patch in plasmin, whereas in, FVIIa, such interactions are not possible. Thus, the specificity of KD1, for plasmin is attributable to hydrophobic and direct electrostatic, interactions. For trypsin, hydrophobic interactions are intact, and, electrostatic interactions are weak, whereas for FVIIa, hydrophobic, interactions are missing, and electrostatic interactions are partially, intact. These findings provide insight into the protease selectivity of, KD1.
+Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 inhibits trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor with Ki values of 13, 3, and 1640 nM, respectively. To investigate the molecular specificity of KD1, crystals of the complex of KD1 with bovine beta-trypsin were obtained that diffracted to 1.8 A. The P1 residue Arg-15 (bovine pancreatic trypsin inhibitor numbering) in KD1 interacts with Asp-189 (chymotrypsin numbering) and with the carbonyl oxygens of Gly-219 and Ogamma of Ser-190. Leu-17, Leu-18, Leu-19, and Leu-34 in KD1 make van der Waals contacts with Tyr-39, Phe-41, and Tyr-151 in trypsin, forming a hydrophobic interface. Molecular modeling indicates that this complementary hydrophobic patch is composed of Phe-37, Met-39, and Phe-41 in plasmin, whereas in FVIIa/tissue factor, it is essentially absent. Arg-20, Tyr-46, and Glu-39 in KD1 interact with trypsin through ordered water molecules. In contrast, insertions in the 60-loop in plasmin and FVIIa allow Arg-20 of KD1 to directly interact with Glu-60 in plasmin and Asp-60 in FVIIa. Moreover, Tyr-46 in KD1 electrostatically interacts with Lys-60A and Arg-60D in plasmin and Lys-60A in FVIIa. Glu-39 in KD1 interacts directly with Arg-175 of the basic patch in plasmin, whereas in FVIIa, such interactions are not possible. Thus, the specificity of KD1 for plasmin is attributable to hydrophobic and direct electrostatic interactions. For trypsin, hydrophobic interactions are intact, and electrostatic interactions are weak, whereas for FVIIa, hydrophobic interactions are missing, and electrostatic interactions are partially intact. These findings provide insight into the protease selectivity of KD1.
 ==About this Structure==
-ZR0 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ZR0 OCA].
+ZR0 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZR0 OCA].
 ==Reference==
@@ Line 16: / Line 15: @@
 [[Category: Protein complex]]
 [[Category: Trypsin]]
-[[Category: Bajaj, S.P.]]
+[[Category: Bajaj, S P.]]
 [[Category: Cascio, D.]]
-[[Category: Chand, H.S.]]
+[[Category: Chand, H S.]]
 [[Category: Kisiel, W.]]
-[[Category: Schmidt, A.E.]]
+[[Category: Schmidt, A E.]]
 [[Category: CA]]
 [[Category: serine protease; complex of serine protease/inhibitor; kunitz type inhibitor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:39:30 2007''
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