4JZ1

Crystal Structure of Matriptase in complex with Inhibitor

Summary for 4JZ1

• Entry DOI: 10.2210/pdb4jz1/pdb
• Related: 4JYT 4JZI
• Descriptor: Suppressor of tumorigenicity 14 protein, 4,4'-[(3-{[(4-fluorophenyl)sulfonyl]amino}pyridine-2,6-diyl)bis(oxy)]dibenzenecarboximidamide (3 entities in total)
• Functional Keywords: matriptase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane ; Single-pass type II membrane protein : Q9Y5Y6
• Total number of polymer chains: 1
• Total formula weight: 26984.29

Authors

Subramanya, H.S.,Ravi, B.C.,Ashok, K.N.,Chakshusmathi, G.,Ramesh, K.S. (deposition date: 2013-04-02, release date: 2014-02-26, Last modification date: 2024-10-30)

Primary citation

Goswami, R.,Mukherjee, S.,Wohlfahrt, G.,Ghadiyaram, C.,Nagaraj, J.,Chandra, B.R.,Sistla, R.K.,Satyam, L.K.,Samiulla, D.S.,Moilanen, A.,Subramanya, H.S.,Ramachandra, M.
Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors
ACS MED.CHEM.LETT., 4:1152-1157, 2013

PubMed Abstract: Matriptase belongs to trypsin-like serine proteases involved in matrix remodeling/degradation, growth regulation, survival, motility, and cell morphogenesis. Herein, we report a structure-based approach, which led to the discovery of sulfonamide and amide derivatives of pyridyl bis(oxy)benzamidine as potent and selective matriptase inhibitors. Co-crystal structures of selected compounds in complex with matriptase supported compound designing. Additionally, WaterMap analyses indicated the possibility of occupying a distinct pocket within the catalytic domain, exploration of which resulted in >100-fold improvement in potency. Co-crystal structure of 10 with matriptase revealed critical interactions leading to potent target inhibition and selectivity against other serine proteases.

PubMed: 24900621
DOI: 10.1021/ml400213v

Experimental method

X-RAY DIFFRACTION (1.9 Å)