2cf8: Difference between revisions
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[[Image:2cf8.gif|left|200px]] | [[Image:2cf8.gif|left|200px]] | ||
''' | {{Structure | ||
|PDB= 2cf8 |SIZE=350|CAPTION= <scene name='initialview01'>2cf8</scene>, resolution 1.30Å | |||
|SITE= <scene name='pdbsite=AC1:Ca+Binding+Site+For+Chain+H'>AC1</scene> | |||
|LIGAND= <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ESH:4-+[(1R,3AS,4R,8AS,8BR)-+2-+(4-CHLOROBENZYL)-+1-+ISOPROPYL-+3-+OXODECAHYDROPYRROLO[3,4-+A]PYRROLIZIN-+4-+YL]BENZENECARBOXIMIDAMIDE'>ESH</scene> and <scene name='pdbligand=SIN:SUCCINIC ACID'>SIN</scene> | |||
|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] | |||
|GENE= | |||
}} | |||
'''THROMBIN-METHOXY''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2CF8 is a [ | 2CF8 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=2CF8 OCA]. | ||
==Reference== | ==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:[http:// | 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]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:14:35 2008'' | ||
Revision as of 17:14, 20 March 2008
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| , resolution 1.30Å | |||||||
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| Sites: | |||||||
| Ligands: | , , and | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
THROMBIN-METHOXY
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
2CF8 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
Page seeded by OCA on Thu Mar 20 16:14:35 2008
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Protein complex
- Thrombin
- Banner, D W.
- Diederich, F.
- Hoffmann-Roeder, A.
- Kansy, M.
- Obst-Sander, U.
- Olsen, J A.
- Schweizer, E.
- Wagner, B.
- CA
- ESH
- NA
- SIN
- Acute phase
- Blood coagulation
- Calcium-binding
- Complex hydrolase/inhibitor
- Glycoprotein
- Hydolase
- Serine protease
- Serine protease inhibitor complex