| Abstract
| - Serpins are a class of protease inhibitors that initially fold to a metastable structure andsubsequently undergo a large conformational change to a stable structure when they inhibit their targetproteases. How serpins are able to achieve this remarkable conformational rearrangement is still notunderstood. To address the question of how the dynamic properties of the metastable form may facilitatethe conformational change, hydrogen/deuterium exchange and mass spectrometry were employed to probethe conformational dynamics of the serpin human α1-antitrypsin (α1AT). It was found that the F helix,which in the crystal structure appears to physically block the conformational change, is highly dynamicin the metastable form. In particular, the C-terminal half of the F helix appears to spend a substantialfraction of time in a partially unfolded state. In contrast, β-strands 3A and 5A, which must separate toaccommodate insertion of the reactive center loop (RCL), are not conformationally flexible in the metastablestate but are rigid and stable. The conformational lability required for loop insertion must therefore betriggered during the inhibition reaction. β-strand 1C, which anchors the distal end of the RCL and thusprevents transition to the so-called latent form, is also stable, consistent with the observation that α1ATdoes not spontaneously adopt the latent form. A surprising degree of flexibility is seen in β-strand 6A,and it is speculated that this flexibility may deter the formation of edge−edge polymers.
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