4X8S

FACTOR VIIA IN COMPLEX WITH THE INHIBITOR 4-BROMO-2-METHOXYPHENOL

Summary for 4X8S

• Entry DOI: 10.2210/pdb4x8s/pdb
• Related: 4X8T 4X8U 4X8V
• Descriptor: Factor VIIa (Heavy Chain), Factor VIIa (Light Chain), 4-bromo-2-methoxyphenol, ... (7 entities in total)
• Functional Keywords: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium- binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P08709 P08709
• Total number of polymer chains: 2
• Total formula weight: 35037.73

Authors

Wei, A. (deposition date: 2014-12-10, release date: 2015-03-25, Last modification date: 2015-04-08)

Primary citation

Cheney, D.L.,Bozarth, J.M.,Metzler, W.J.,Morin, P.E.,Mueller, L.,Newitt, J.A.,Nirschl, A.H.,Rendina, A.R.,Tamura, J.K.,Wei, A.,Wen, X.,Wurtz, N.R.,Seiffert, D.A.,Wexler, R.R.,Priestley, E.S.
Discovery of Novel P1 Groups for Coagulation Factor VIIa Inhibition Using Fragment-Based Screening.
J.Med.Chem., 58:2799-2808, 2015

PubMed Abstract: A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.

PubMed: 25764119
DOI: 10.1021/jm501982k

Experimental method

X-RAY DIFFRACTION (2.1 Å)