4GA7

Crystal structure of human serpinB1 mutant

Summary for 4GA7

• Entry DOI: 10.2210/pdb4ga7/pdb
• Related: 4GAW
• Descriptor: Leukocyte elastase inhibitor (2 entities in total)
• Functional Keywords: serpin, conformational change, serine protease inhibitor, cathepsin g inhibitor, chymase inhibitor, chymotrypsin inhibitor, hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): P30740
• Total number of polymer chains: 2
• Total formula weight: 87877.51

Authors

Wang, L.,Li, Q.,Wu, L.,Zhang, K.,Tong, L.,Sun, F.,Fan, Z. (deposition date: 2012-07-25, release date: 2013-01-16, Last modification date: 2024-10-30)

Primary citation

Wang, L.,Li, Q.,Wu, L.,Liu, S.,Zhang, Y.,Yang, X.,Zhu, P.,Zhang, H.,Zhang, K.,Lou, J.,Liu, P.,Tong, L.,Sun, F.,Fan, Z.
Identification of SERPINB1 as a physiological inhibitor of human granzyme H
J.Immunol., 190:1319-1330, 2013

PubMed Abstract: The granzyme/perforin pathway is a major mechanism for cytotoxic lymphocytes to eliminate virus-infected and tumor cells. The balance between activation and inhibition of the proteolytic cascade must be tightly controlled to avoid self damage. Granzyme H (GzmH) is constitutively expressed in NK cells and induces target cell death; however, how GzmH activity is regulated remains elusive. We reported earlier the crystal structures of inactive D102N-GzmH alone and in complex with its synthetic substrate and inhibitor, as well as defined the mechanisms of substrate recognition and enzymatic activation. In this study, we identified SERPINB1 as a potent intracellular inhibitor for GzmH. Upon cleavage of the reactive center loop at Phe(343), SERPINB1 forms an SDS-stable covalent complex with GzmH. SERPINB1 overexpression suppresses GzmH- or LAK cell-mediated cytotoxicity. We determined the crystal structures of active GzmH and SERPINB1 (LM-DD mutant) in the native conformation to 3.0- and 2.9-Å resolution, respectively. Molecular modeling reveals the possible conformational changes in GzmH for the suicide inhibition. Our findings provide new insights into the inhibitory mechanism of SERPINB1 against human GzmH.

PubMed: 23269243
DOI: 10.4049/jimmunol.1202542

Experimental method

X-RAY DIFFRACTION (2.9 Å)