Serpin fold

Figure 6,22 Schematic diagram of the structure of ovalbumin which illustrates the serpin fold. The structure is built up of a compact body of three antiparallel p sheets,...

The setpin fold comprises a compact body of three antiparallel p sheets, A, B and C, which ate partly coveted by a helices (Figure 6.22). In the structure of the uncleaved form of ovalbumin, which can be regarded as the canonical structure of the serpins, sheet A has five strands. The flexible loop starts at the end of strand number 5 of p sheet A (plS in Figure 6.22), then... 

An enzyme reaction intermediate (Enz—O—C(0)R or Enz—S—C(O)R), formed by a carboxyl group transfer (e.g., from a peptide bond or ester) to a hydroxyl or thiol group of an active-site amino acyl residue of the enzyme. Such intermediates are formed in reactions catalyzed by serine proteases transglutaminase, and formylglyci-namide ribonucleotide amidotransferase . Acyl-enzyme intermediates often can be isolated at low temperatures, low pH, or a combination of both. For acyl-seryl derivatives, deacylation at a pH value of 2 is about 10 -fold slower than at the optimal pH. A primary isotope effect can frequently be observed with a C-labeled substrate. If an amide substrate is used, it is possible that a secondary isotope effect may be observed as welF. See also Active Site Titration Serpins (Inhibitory Mechanism)... 

Antithrombin is a member of the SERPIN superfamily of proteins, which includes the inhibitors a2 an1 Pbsniin, ar antichymotrypsin, and a -proteinase inhibitor (79). Antithrombin is considered to be the primary inhibitor of coagulation (80) and targets most coagulation proteases as well as the enzymes trypsin, plasmin, and kallikrein (81). Inhibition takes place when a stoichiometric complex between the active site serine of the protease and the ARG393-SER394 bond of antithrombin forms (82,83), The tertiary structure of antithrombin resembles a,-antitrypsin in that it is folded into N-terminal domain helices and (3-sheets. This tertiary structure is maintained by the formation of three disulfide bonds (71). Four glycosylation sites exist on human... 

Whisstock JC, Bottomley SP. Molecular gymnastics serpin structure, folding and misfolding. Curr. Opin. Struct. Biol. 2006 16 761-768. 

CHAPTER 36, FIGURE 7 A group of structurally similar protein inhibitors of the serine proteinases known as SERPINS (SERine Proteinase INhibitors). The structure shown is human antithrombin. The reference SERPIN, a j-proteinase inhibitor or a. -antitrypsin contains -30% a helix (9 helices) and 40% sheet (5 3 sheets). Other members of the SERPIN family contain both additional helices and p sheets. The reactive center loop of antithrombin, residues 378-396, contains the reactive site residues Arg and Ser . Upon reaction with the target proteinase or after cleavage by the target proteinase (a reaction that inactivates the inhibitor without inactivating the proteinase), the reactive center loop folds between the S3 and S5 sheets. 

A completely different example of the serpin CrmA (cytokine response modifier A), which expresses Cowpox virus. The targets of CrmA are members of the caspase family of proteases that either initiate the extrinsic pathway of apoptosis (caspases 8 and 10) or trigger activation of the pro-inflammatory cytokines interleukin-1 p and interleukin-18 (caspase 1). CrmA has the typical fold of a cleaved serpin, even though it lacks the N-terminal half of the A helix, the entire D helix, and a portion of the E helix that are present in all other known serpins. Thus, the inhibitory proteins can be not only drugs. They may also viral countermeasures to host defenses against infection may contribute significantly to the pathology associated with poxvirus infections (Renatus et al, 2000). 

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