1mik
From Proteopedia
(New page: 200px<br /><applet load="1mik" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mik, resolution 1.76Å" /> '''THE ROLE OF WATER MO...) |
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| - | [[Image:1mik.gif|left|200px]]<br /><applet load="1mik" size=" | + | [[Image:1mik.gif|left|200px]]<br /><applet load="1mik" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1mik, resolution 1.76Å" /> | caption="1mik, resolution 1.76Å" /> | ||
'''THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A'''<br /> | '''THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A | + | Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4). |
==About this Structure== | ==About this Structure== | ||
| - | 1MIK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | + | 1MIK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence 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=1MIK OCA]. |
==Reference== | ==Reference== | ||
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[[Category: complex (isomerase/immunosuppressant)]] | [[Category: complex (isomerase/immunosuppressant)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:55:31 2008'' |
Revision as of 11:55, 21 February 2008
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THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A
Overview
Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).
About this Structure
1MIK is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A., Mikol V, Papageorgiou C, Borer X, J Med Chem. 1995 Aug 18;38(17):3361-7. PMID:7650689
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