2oay
From Proteopedia
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==Overview== | ==Overview== | ||
| - | C1 inhibitor, a member of the serpin family, is a major down-regulator of | + | C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded beta-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack. |
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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Angioedema, hereditary OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606860 606860]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: latent serpin; rcl insertion]] | [[Category: latent serpin; rcl insertion]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:16:29 2008'' |
Revision as of 16:16, 21 February 2008
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Crystal structure of latent human C1-inhibitor
Contents |
Overview
C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded beta-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack.
Disease
Known diseases associated with this structure: Angioedema, hereditary OMIM:[606860]
About this Structure
2OAY is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease., Beinrohr L, Harmat V, Dobo J, Lorincz Z, Gal P, Zavodszky P, J Biol Chem. 2007 Jul 20;282(29):21100-9. Epub 2007 May 8. PMID:17488724
Page seeded by OCA on Thu Feb 21 18:16:29 2008
