Literature summary for 3.4.21.75 extracted from

Dahms, S.O.; Arciniega, M.; Steinmetzer, T.; Huber, R.; Than, M.E.
Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism (2016), Proc. Natl. Acad. Sci. USA, 113, 11196-11201 .

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Activating Compound

Activating Compound	Comment	Organism	Structure
additional information	structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism, complex activation mechanism, overview	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified unliganded furin in different functional states, different Ca2+- and inhibitor (3-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(4-amidomethyl)-benzamidine)-bound forms of the enzyme, crystals of human furin are grown in sitting drops mixing equal volumes of 9 mg/ml protein solution and crystallization solution containing 100 mM MES, 200 mM K/NaH2PO4, pH 5.5-6.0, 3-4 M NaCl, and 3% v/v DMSO, the reservoir contains 3-4 M NaCl, for inhibitor binding studies the crystals are soaked with inhibitor and for calcium-studies the crystals are soaked with EDTA and Ca2+, X-ray diffraction structure determination and analysis at 1.8-2.0 A resolution	Homo sapiens

Crystallization (Comment)

Organism

purified unliganded furin in different functional states, different Ca2+- and inhibitor (3-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(4-amidomethyl)-benzamidine)-bound forms of the enzyme, crystals of human furin are grown in sitting drops mixing equal volumes of 9 mg/ml protein solution and crystallization solution containing 100 mM MES, 200 mM K/NaH2PO4, pH 5.5-6.0, 3-4 M NaCl, and 3% v/v DMSO, the reservoir contains 3-4 M NaCl, for inhibitor binding studies the crystals are soaked with inhibitor and for calcium-studies the crystals are soaked with EDTA and Ca2+, X-ray diffraction structure determination and analysis at 1.8-2.0 A resolution

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
3-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(4-amidomethyl)-benzamidine	MI-52, a substrate-analogous, noncovalent inhibitor. The furin-MI-52 complex is highly stable	Homo sapiens
additional information	no inhibition of human furin by DFP, 4-(2-aminoethyl)benzensulfonylfluorid (AEBSF), and PMSF	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Ca2+	strict Ca2+ dependence, calcium-dependent activity regulation of furin	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P09958	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	high substrate selectivity and enzymatic activity of furin	Homo sapiens	?	-	?

Synonyms

Synonyms	Comment	Organism
Proprotein convertase	-	Homo sapiens

General Information

General Information	Comment	Organism
evolution	furin is a member of the prototypical PC family	Homo sapiens
malfunction	an unbalanced activity of proprotein convertases is connected to pathologies like cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases	Homo sapiens
additional information	enzyme modeling by molecular dynamics calculations. Furin shows a complex activation mechanism and exists in at least four defined states: (i) the off state, incompatible with substrate binding as seen in the unliganded enzyme; (ii) the active on state seen in inhibitor-bound furin; and the respective (iii) calcium-free and (iv) calcium-bound forms. The transition from the off to the on state is triggered by ligand binding at subsites S1 to S4 and appears to underlie the preferential recognition of the four-residue sequence motif of furin. Ligation by calcium at the PC-specific binding site II influences the active-site geometry and determines the rotamer state of the oxyanion hole-forming Asn295, and adds a second level of the activity modulation of furin. Analysis of substrate induced structural rearrangements of furin, the spatial restrictions at and around the catalytic serine residue 368 of furin are structurally reminiscent of typical trypsin-like proteases, overview. Hotspots of conformational changes include the catalytic residues His194, Ser368, Asn295 of the oxyanion hole, the sodium binding site (Thr309 and Ser316), and residues in direct contact with the inhibitor peptide (e.g. the region Ser253-Pro256, the alignment template). Mapping of the Calpha displacement to the surface of the structure induced by inhibitor binding reveals a concerted local rearrangement at the substrate-binding cleft	Homo sapiens
physiological function	proprotein convertases (PCs) are highly specific proteases required for the proteolytic modification of many secreted proteins. Calcium-dependent activity regulation of furin	Homo sapiens