1qmn
From Proteopedia
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ALPHA1-ANTICHYMOTRYPSIN SERPIN IN THE DELTA CONFORMATION (PARTIAL LOOP INSERTION)
Contents |
Overview
The serpins are a family of proteinase inhibitors that play a central role, in the control of proteolytic cascades. Their inhibitory mechanism depends, on the intramolecular insertion of the reactive loop into beta-sheet A, after cleavage by the target proteinase. Point mutations within the, protein can allow aberrant conformational transitions characterized by, beta-strand exchange between the reactive loop of one molecule and, beta-sheet A of another. These loop-sheet polymers result in diseases as, varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we, recently have shown that they underlie an early-onset dementia. We report, here the biochemical characteristics and crystal structure of a naturally, occurring variant (Leu-55-Pro) of the plasma serpin, alpha(1)-antichymotrypsin trapped as an inactive intermediate. The, structure demonstrates a serpin configuration with partial insertion of, the reactive loop into beta-sheet A. The lower part of the sheet is filled, by the last turn of F-helix and the loop that links it to s3A. This, conformation matches that of proposed intermediates on the pathway to, complex and polymer formation in the serpins. In particular, this, intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma alpha(1)-antichymotrypsin, associated with chronic obstructive pulmonary disease in patients with the, Leu-55-Pro mutation.
Disease
Known diseases associated with this structure: Alpha-1-antichymotrypsin deficiency OMIM:[107280], Cerebrovascular disease, occlusive OMIM:[107280]
About this Structure
1QMN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease., Gooptu B, Hazes B, Chang WS, Dafforn TR, Carrell RW, Read RJ, Lomas DA, Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):67-72. PMID:10618372
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