2cf9

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[[Image:2cf9.gif|left|200px]]<br /><applet load="2cf9" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2cf9.gif|left|200px]]
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caption="2cf9, resolution 1.79&Aring;" />
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'''THROMBIN-METHOXY2'''<br />
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{{Structure
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|PDB= 2cf9 |SIZE=350|CAPTION= <scene name='initialview01'>2cf9</scene>, resolution 1.79&Aring;
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|SITE= <scene name='pdbsite=AC1:Ca+Binding+Site+For+Chain+H'>AC1</scene>
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|LIGAND= <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene> and <scene name='pdbligand=348:4-[(1R,3AS,4R,8AS,8BR)-1-ISOPROPYL-2-(4-METHOXYBENZYL)-3-OXODECAHYDROPYRROLO[3,4-A]PYRROLIZIN-4-YL]BENZENECARBOXIMIDAMIDE'>348</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5]
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|GENE=
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}}
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'''THROMBIN-METHOXY2'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2CF9 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</scene>, <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=SIN:'>SIN</scene> and <scene name='pdbligand=348:'>348</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Known structural/functional Site: <scene name='pdbsite=AC1:Ca+Binding+Site+For+Chain+H'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CF9 OCA].
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2CF9 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CF9 OCA].
==Reference==
==Reference==
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Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors., Schweizer E, Hoffmann-Roder A, Olsen JA, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, Org Biomol Chem. 2006 Jun 21;4(12):2364-75. Epub 2006 May 10. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16763681 16763681]
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Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors., Schweizer E, Hoffmann-Roder A, Olsen JA, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, Org Biomol Chem. 2006 Jun 21;4(12):2364-75. Epub 2006 May 10. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16763681 16763681]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: serine protease inhibitor complex]]
[[Category: serine protease inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:48:00 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:14:38 2008''

Revision as of 14:14, 20 March 2008

Image:2cf9.gif


PDB ID 2cf9

Drag the structure with the mouse to rotate
, resolution 1.79Å
Sites:
Ligands: , , and
Activity: Thrombin, with EC number 3.4.21.5
Coordinates: save as pdb, mmCIF, xml



THROMBIN-METHOXY2


Contents

Overview

Two series of tricyclic inhibitors of the serine protease thrombin, imides (+/-)-1-(+/-)-8 and lactams (+/-)-9-(+/-)-13, were analysed to evaluate contributions of orthogonal multipolar interactions with the backbone C=O moiety of Asn98 to the free enthalpy of protein-ligand complexation. The lactam derivatives are much more potent and more selective inhibitors (K(i) values between 0.065 and 0.005 microM, selectivity for thrombin over trypsin between 361- and 1609-fold) than the imide compounds (Ki values between 0.057 and 23.7 microM, selectivity for thrombin over trypsin between 3- and 67-fold). The increase in potency and selectivity is explained by the favorable occupancy of the P-pocket of thrombin by the additional isopropyl substituent in the lactam derivatives. The nature of the substituent on the benzyl ring filling the D pocket strongly influences binding potency in the imide series, with Ki values increasing in the sequence: F < OCH2O < Cl < H < OMe < OH < N(pyr)<< Br. This sequence can be explained by both steric fit and the occurrence of orthogonal multipolar interactions with the backbone C[double bond, length as m-dash]O moiety of Asn98. In contrast, the substituent on the benzyl ring hardly affects the ligand potency in the lactam series. This discrepancy was clarified by the comparison of X-ray structures solved for co-crystals of thrombin with imide and lactam ligands. Whereas the benzyl substituents in the imide inhibitors are sufficiently close (< or =3.5 Angstroms) to the C=O group of Asn98 to allow for attractive orthogonal multipolar interactions, the distances in the lactam series are too large (> or =4 Angstroms) for attractive dipolar contacts to be effective.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

2CF9 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors., Schweizer E, Hoffmann-Roder A, Olsen JA, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, Org Biomol Chem. 2006 Jun 21;4(12):2364-75. Epub 2006 May 10. PMID:16763681

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