Currently our Section concentrates on investigation of the quality of crystal and cryoEM structures deposited in the Protein Data Bank, with the aim of flagging models that exhibit problems such as poor fit to the map, missing water molecules, improperly modeled ligands, or even duplicated entries.

Crystallographic Studies of Proteases and Their Inhibitors

Crystallographic studies of proteases had been in the past an important area of research of this Section. We have been particularly active in the investigation of structure-function relationship in aspartic proteases, including clinically important retroviral enzymes. We have investigated structure-function relationship in retroviral proteases from several sources, such as HIV-1, FIV, RSV, EIAV, HTLV-1, and XMRV. Cockroach allergen Bla g 2 was shown to be an inactive aspartic protease and we solved its structure by itself, and in a complex with several specific antibodies. We have determined the structure of a unique histoaspartic protease, an enzyme with the pepsin fold, but a vastly different mechanism. We have been investigating serine-carboxyl peptidases (sedolisins), a family that was first characterized based on crystal structures solved in this laboratory and that is found in many different organisms.

We were also investigating the bacterial ATP-dependent protease Lon, having found that its proteolytic domain has a unique fold and thus establishes a new family of proteases with a Ser-Lys catalytic dyad. We have solved the structures of the proteolytic domain of A and B type Lon proteases, encoded by E. coli and Archaeoglobus fulgidus, as well as the N-terminal and α domains of E. coli Lon. We have been engaged in structural and biochemical studies of serine protease inhibitors EcTI,BbKI, and CrataBL, the latter being both an inhibitor and a lectin with potent anticancer properties.

Our extramural collaborators include Mariusz Jaskolski, D.Sc., Adam Mickiewicz University, Poznan, Poland; Wladek Minor, Ph. D., University of Virginia, Charlottesville, VA; and Tatyana Rotanova, D.Sc., Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.