The Factor VII Zymogen Structure Reveals Reregistration of β Strands during Activation

Eigenbrot, Charles; Kirchhofer, Daniel; Dennis, Mark S.; Santell, Lydia; Lazarus, Robert A.; Stamos, Jennifer L.; Ultsch, Mark

doi:10.1016/s0969-2126(01)00624-4

Cited by 93 publications

(122 citation statements)

References 45 publications

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“…The presence of tissue factor (TF) enhances the activity of factor VIIa (FVIIa) toward FX by a factor of approximately 10 5 if full length [1,2] and by a factor of approximately 76 in the soluble (TFs), truncated form [3]. The activation of FVII is also greatly enhanced by the presence of TF [4].…”

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confidence: 99%

“…Additionally, the zymogen structure has a bound non-active site inhibitor; this inhibitor has also been shown to block the binding of TF to FVIIa [12]. The zymogen structure [10] inspired others to test the hypothesis by designing mutations that blocked the shift between the two proposed forms in FVIIa [13]; the results of these experiments did not substantiate the FVIIa two-state hypothesis as the mutations appeared to have little effect on FX cleavage rates.…”

mentioning

confidence: 99%

“…The publication of the structural data on the FVII zymogen [10] that led to the two-state hypothesis for FVIIa compares the FVIIa/TF structure and the FVII zymogen structure. Only one set of crystal contacts is defined [10], these contacts being away either from the inhibitor (A183) binding site or that of local conformation change.…”

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confidence: 99%

“…Intermolecular contacts between the exosite inhibitor on one FVII molecule (FVII-1) and a second FVII molecule (FVII-2) in the same unit cell. (a) the X-ray crystal structure [10]. The inhibitor peptide (A183-2) bound to FVII-2 is shown in green; the residues of FVII (1) End-stage renal disease (ESRD) patients experience a high mortality rate from cardiovascular diseases [1,2].…”

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confidence: 99%

“…The high prevalence of atherosclerosis in ESRD has been well documented [9,10]. Plasminogen activator inhibitor-1 (PAI-1), a mediator of thrombosis and one of the risk markers for coronary heart disease, is enhanced in atherosclerotic plaques and co-localizes with macrophages [11].…”

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A reconsideration of the evidence for structural reorganization in FVII zymogen

Perera

Pedersen

2005

Journal of Thrombosis and Haemostasis

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The presence of tissue factor (TF) enhances the activity of factor VIIa (FVIIa) toward FX by a factor of approximately 10 5 if full length [1,2] and by a factor of approximately 76 in the soluble (TFs), truncated form [3]. The activation of FVII is also greatly enhanced by the presence of TF [4]. As the initial X-ray crystal structure of the complex of TFs/FVIIa/inhibitor revealed that TF does not bind at or near the active site of FVIIa [5], there has been a substantial interest in the question: how is the allosteric effect of TF (or TFs) on FVIIa manifested? We have previously built equilibrated solution models of FVII zymogen [6], FVIIa/TFs [7] and TFs/FVIIa/FXa [8] so as to extend the X-ray data into the realm of short-time dynamics (less than a few nanoseconds) to investigate local changes. Likewise, others have provided mutational studies that provide clues for the underlying nature of the allosteric effect [3,9]. Recently, it has been proposed [10] that FVII/FVIIa exists in two forms, one of which is competent to be enhanced by TF, and the other not. The existence of these two forms was suggested [10,11] as a result of a structural study in which it was found that FVII zymogen (serine protease + egf2 domains) has a local conformational change -a novel registration of b-sheets B2-A2 -not seen in the explicit FVIIa structures. The competent form was taken to be that seen in the original FVIIa/TFs structure; the incompetent form was taken to be that seen in the FVII zymogen structure [10,11]. Additionally, the zymogen structure has a bound non-active site inhibitor; this inhibitor has also been shown to block the binding of TF to FVIIa [12]. The zymogen structure [10] inspired others to test the hypothesis by designing mutations that blocked the shift between the two proposed forms in FVIIa [13]; the results of these experiments did not substantiate the FVIIa two-state hypothesis as the mutations appeared to have little effect on FX cleavage rates.The publication of the structural data on the FVII zymogen [10] that led to the two-state hypothesis for FVIIa compares the FVIIa/TF structure and the FVII zymogen structure. Only one set of crystal contacts is defined [10], these contacts being away either from the inhibitor (A183) binding site or that of local conformation change. When we did (by several independent codes) a tally of all of the crystal contacts (pdb ¼ 1JBU), we were surprised to find that a second molecule in the unit cell (four molecules per unit cell) contacts the first molecule, the points of contact being through several regions of the zymogen of the first FVII molecule with the inhibitor bound to the second zymogen FVII molecule. Several contacts are strong hydrogen bonds. What is vitally important for this discussion is that the point of contact on the first molecule occurs at precisely the location of the local conformational change observed in the structural work for FVII. The interaction of the peptide bound to the second zymogen molecule with the first zymogen is clearly seen in Fig. 1a...

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confidence: 99%

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confidence: 99%

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A reconsideration of the evidence for structural reorganization in FVII zymogen

Perera

Pedersen

2005

Journal of Thrombosis and Haemostasis

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X‐Ray Crystallography in Drug Discovery

Livingston¹,

Buchanan²,

D’Amico³

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

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The focus of this chapter is the methods, recent advances, and the applications of X‐ray protein crystallography in the discovery of new drug targets and candidate drugs. It begins with a basic description of the various steps involved in solving a structure, including recent advances in technique and technology, and the major challenges that are faced in executing the process. The underlying theory, various crystallization methods, data collection equipment and techniques, and computational reduction of the data to give the final structure are all covered in this section. The accessible databases that contain large collections of structures are also described. The application to drug discovery is then briefly addressed with a discussion of co‐crystallization methods and issues, which is followed by a comprehensive table enumerating the published structures of the known drug targets and close homologs. Applications to discovering and validating protein targets of therapeutic relevance are then covered in a section on the very new field of structural genomics. Genome annotation by structural homology, elucidating pathways and the potential for the rational design of multitarget drugs, and advances in the field of protein structure modeling that are enabled by crystallographic databases are described and exemplified with very recent results from the field.

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Allosteric Regulation of Proteases

et al. 2008

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Allostery is a basic principle of control of enzymatic activities based on the interaction of a protein or small molecule at a site distinct from an enzyme's active center. Allosteric modulators represent an alternative approach to the design and synthesis of small-molecule activators or inhibitors of proteases and are therefore of wide interest for medicinal chemistry. The structural bases of some proteinaceous and small-molecule allosteric protease regulators have already been elucidated, indicating a general mechanism that might be exploitable for future rational design of small-molecule effectors.

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The Factor VII Zymogen Structure Reveals Reregistration of β Strands during Activation

Cited by 93 publications

References 45 publications

A reconsideration of the evidence for structural reorganization in FVII zymogen

A reconsideration of the evidence for structural reorganization in FVII zymogen

X‐Ray Crystallography in Drug Discovery

Allosteric Regulation of Proteases

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