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Cathepsin B (EC 3.4.22.1) is one of the most versatile human cysteine cath-epsins. It is important for intracellular protein degradation under normal conditions and is involved in a number of pathological processes. The occluding loop makes cathepsin B unique among cysteine cathepsins. | Stef in A displaces the occluding loop of cathepsin B only by as much as required to bind to the active site cleft Miha Renko Urska Pozgan Dusana Majera and Dusan Turk Department of Biochemistry and Molecular and StructuralBiology Jozef Stefan Institute Ljubljana Slovenia Keywords cathepsin B complex conformational flexibility crystal structure occluding loop stefin A Correspondence D. Turk Department of Biochemistry and Molecular and Structural Biology Jozef Stefan Institute Jamova 39 SI-1000 Ljubljana Slovenia Fax 386 1 477 3984 Tel 386 1 477 3215 E-mail dusan.turk@ijs.si Database The coordinates and structure factors are available in the Protein Data Bank database under accession number 3K9M Received 14 June 2010 revised 11 August 2010 accepted 16 August 2010 doi 10.1111 j.1742-4658.2010.07824.x Cathepsin B EC 3.4.22.1 is one of the most versatile human cysteine cathepsins. It is important for intracellular protein degradation under normal conditions and is involved in a number of pathological processes. The occluding loop makes cathepsin B unique among cysteine cathepsins. This 20 residue long insertion imbedded into the papain-like protease scaffold restricts access to the active site cleft and endows cathepsin B with its carboxydipeptidase activity. Nevertheless the enzyme also exhibits endopeptidase activity and is inhibited by stefins and cystatins. To clarify the structural properties of the occluding loop upon the binding of stefins we determined the crystal structure of the complex between wild-type human stefin A and wild-type human cathepsin B at 2.6 A resolution. The papainlike part of cathepsin B structure remains unmodified whereas the occluding loop residues are displaced. The part enclosed by the disulfide bridge containing histidines 110 and 111 i.e. the lasso part is rotated by 45 away from its original position. A comparison of the structure of the unli-ganded cathepsin B with the structure of the proenzyme its complexes with chagasin and .
