{"entry": {"accession": "MF7000986", "general": {"name": "SIV protease with inhibitor SB203386", "pdb_id": "1tcw", "exp_method": "X-ray", "resolution": "2.40", "assembly": "Homodimer", "source_organism": "Simian immunodeficiency virus", "publication": {"pmid": "8756683", "authors": "Hoog SS, Towler EM, Zhao B, Doyle ML, Debouck C, Abdel-Meguid SS", "title": "Human immunodeficiency virus protease ligand specificity conferred by residues outside of the active site cavity.", "journal": "Biochemistry", "year": "1996", "issue": "32", "volume": "35", "pages": "10279-86", "abstract": "To gain greater understanding of the structural basis of human immunodeficiency virus (HIV) protease ligand specificity, we have crystallized and determined the structures of the HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant and simian immunodeficiency virus (SIV) protease in complex with SB203386, a tripeptide analogue inhibitor containing a C-terminal imidazole substituent as an amide bond isostere. SB203386 is a potent inhibitor of HIV-1 protease (Ki = 18 nM) but shows decreased inhibition of the HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant (Ki = 112 nM) and SIV protease (Ki = 960 nM). Although SB203386 binds in the active site cavity of the triple mutant in a similar fashion to its binding to the wild-type HIV-1 protease [Abdel-Meguid et al. (1994) Biochemistry 33, 11671], it binds to SIV protease in an unexpected mode showing two inhibitor molecules each binding to half of the active site. Comparison of these two structures and that of the wild-type HIV-1 protease bound to SB203386 reveals that HIV protease ligand specificity is imparted by residues outside of the catalytic pocket, which causes subtle changes in its shape. Furthermore, this work illustrates the importance of structural studies in order to understand the structure-activity relationship (SAR) between related enzymes."}}, "function": {"molecular_function": {"go": [{"accession": "GO:0004190", "name": "aspartic-type endopeptidase activity"}, {"accession": "GO:0003677", "name": "DNA binding"}, {"accession": "GO:0003887", "name": "DNA-directed DNA polymerase activity"}, {"accession": "GO:0004533", "name": "exoribonuclease H activity"}, {"accession": "GO:0035613", "name": "RNA stem-loop binding"}, {"accession": "GO:0003964", "name": "RNA-directed DNA polymerase activity"}, {"accession": "GO:0004523", "name": "RNA-DNA hybrid ribonuclease activity"}, {"accession": "GO:0005198", "name": "structural molecule activity"}, {"accession": "GO:0008270", "name": "zinc ion binding"}]}, "cellular_component": {"go": [{"accession": "GO:0043657", "name": "host cell"}, {"accession": "GO:0030430", "name": "host cell cytoplasm"}, {"accession": "GO:0042025", "name": "host cell nucleus"}, {"accession": "GO:0020002", "name": "host cell plasma membrane"}, {"accession": "GO:0016020", "name": "membrane"}, {"accession": "GO:0019013", "name": "viral nucleocapsid"}]}, "biological_process": {"go": [{"accession": "GO:0015074", "name": "DNA integration"}, {"accession": "GO:0006310", "name": "DNA recombination"}, {"accession": "GO:0075713", "name": "establishment of integrated proviral latency"}, {"accession": "GO:0006508", "name": "proteolysis"}, {"accession": "GO:0046718", "name": "symbiont entry into host cell"}, {"accession": "GO:0039657", "name": "symbiont-mediated suppression of host gene expression"}, {"accession": "GO:0044826", "name": "viral genome integration into host DNA"}, {"accession": "GO:0075732", "name": "viral penetration into host nucleus"}]}}, "macromolecules": {"general": {"nr_of_chains": "2", "nr_of_unique_protein_segments": "1", "class": "Homooligomeric enzymes", "subclass": "Homodimeric enzymes", "note": "All chains according to the most probable oligomerization state stored in PDBe were considered."}, "chain": [{"id": "A", "name": "Gag-Pol polyprotein", "source_organism": "Simian immunodeficiency virus", "uniprot": {"id": "P05896", "start": "498", "end": "596", "coverage": "6%", "sequence": "MGARNSVLSGKKADELEKIRLRPGGKKKYMLKHVVWAANELDRFGLAESLLENKEGCQKILSVLAPLVPTGSENLKSLYNTVCVIWCIHAEEKVKHTEEAKQIVQRHLVMETGTAETMPKTSRPTAPFSGRGGNYPVQQIGGNYTHLPLSPRTLNAWVKLIEEKKFGAEVVSGFQALSEGCLPYDINQMLNCVGDHQAAMQIIRDIINEEAADWDLQHPQQAPQQGQLREPSGSDIAGTTSTVEEQIQWMYRQQNPIPVGNIYRRWIQLGLQKCVRMYNPTNILDVKQGPKEPFQSYVDRFYKSLRAEQTDPAVKNWMTQTLLIQNANPDCKLVLKGLGTNPTLEEMLTACQGVGGPGQKARLMAEALKEALAPAPIPFAAAQQKGPRKPIKCWNCGKEGHSARQCRAPRRQGCWKCGKMDHVMAKCPNRQAGFFRPWPLGKEAPQFPHGSSASGADANCSPRRTSCGSAKELHALGQAAERKQREALQGGDRGFAAPQFSLWRRPVVTAHIEGQPVEVLLDTGADDSIVTGIELGPHYTPKIVGGIGGFINTKEYKNVEIEVLGKRIKGTIMTGDTPINIFGRNLLTALGMSLNLPIAKVEPVKSPLKPGKDGPKLKQWPLSKEKIVALREICEKMEKDGQLEEAPPTNPYNTPTFAIKKKDKNKWRMLIDFRELNRVTQDFTEVQLGIPHPAGLAKRKRITVLDIGDAYFSIPLDEEFRQYTAFTLPSVNNAEPGKRYIYKVLPQGWKGSPAIFQYTMRHVLEPFRKANPDVTLVQYMDDILIASDRTDLEHDRVVLQLKELLNSIGFSSPEEKFQKDPPFQWMGYELWPTKWKLQKIELPQRETWTVNDIQKLVGVLNWAAQIYPGIKTKHLCRLIRGKMTLTEEVQWTEMAEAEYEENKIILSQEQEGCYYQESKPLEATVIKSQDNQWSYKIHQEDKILKVGKFAKIKNTHTNGVRLLAHVIQKIGKEAIVIWGQVPKFHLPVEKDVWEQWWTDYWQVTWIPEWDFISTPPLVRLVFNLVKDPIEGEETYYVDGSCSKQSKEGKAGYITDRGKDKVKVLEQTTNQQAELEAFLMALTDSGPKANIIVDSQYVMGIITGCPTESESRLVNQIIEEMIKKTEIYVAWVPAHKGIGGNQEIDHLVSQGIRQVLFLEKIEPAQEEHSKYHSNIKELVFKFGLPRLVAKQIVDTCDKCHQKGEAIHGQVNSDLGTWQMDCTHLEGKIVIVAVHVASGFIEAEVIPQETGRQTALFLLKLASRWPITHLHTDNGANFASQEVKMVAWWAGIEHTFGVPYNPQSQGVVEAMNHHLKNQIDRIREQANSVETIVLMAVHCMNFKRRGGIGDMTPAERLINMITTEQEIQFQQSKNSKFKNFRVYYREGRDQLWKGPGELLWKGEGAVILKVGTDIKVVPRRKAKIIKDYGGGKEMDSSSHMEDTGEAREVA", "length": "1448"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "86", "region_end": "94"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "2", "region_end": "3"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "10", "region_end": "15"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "18", "region_end": "24"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "32", "region_end": "33"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "43", "region_end": "48"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "53", "region_end": "66"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "69", "region_end": "77"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "84", "region_end": "85"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "96", "region_end": "98"}, {"region_type": "pfam", "region_id": "PF00077", "region_name": "Retroviral aspartyl protease", "region_start": "503", "region_end": "594"}]}}, {"id": "B", "name": "Gag-Pol polyprotein", "source_organism": "Simian immunodeficiency virus", "uniprot": {"id": "P05896", "start": "498", "end": "596", "coverage": "6%", "sequence": "MGARNSVLSGKKADELEKIRLRPGGKKKYMLKHVVWAANELDRFGLAESLLENKEGCQKILSVLAPLVPTGSENLKSLYNTVCVIWCIHAEEKVKHTEEAKQIVQRHLVMETGTAETMPKTSRPTAPFSGRGGNYPVQQIGGNYTHLPLSPRTLNAWVKLIEEKKFGAEVVSGFQALSEGCLPYDINQMLNCVGDHQAAMQIIRDIINEEAADWDLQHPQQAPQQGQLREPSGSDIAGTTSTVEEQIQWMYRQQNPIPVGNIYRRWIQLGLQKCVRMYNPTNILDVKQGPKEPFQSYVDRFYKSLRAEQTDPAVKNWMTQTLLIQNANPDCKLVLKGLGTNPTLEEMLTACQGVGGPGQKARLMAEALKEALAPAPIPFAAAQQKGPRKPIKCWNCGKEGHSARQCRAPRRQGCWKCGKMDHVMAKCPNRQAGFFRPWPLGKEAPQFPHGSSASGADANCSPRRTSCGSAKELHALGQAAERKQREALQGGDRGFAAPQFSLWRRPVVTAHIEGQPVEVLLDTGADDSIVTGIELGPHYTPKIVGGIGGFINTKEYKNVEIEVLGKRIKGTIMTGDTPINIFGRNLLTALGMSLNLPIAKVEPVKSPLKPGKDGPKLKQWPLSKEKIVALREICEKMEKDGQLEEAPPTNPYNTPTFAIKKKDKNKWRMLIDFRELNRVTQDFTEVQLGIPHPAGLAKRKRITVLDIGDAYFSIPLDEEFRQYTAFTLPSVNNAEPGKRYIYKVLPQGWKGSPAIFQYTMRHVLEPFRKANPDVTLVQYMDDILIASDRTDLEHDRVVLQLKELLNSIGFSSPEEKFQKDPPFQWMGYELWPTKWKLQKIELPQRETWTVNDIQKLVGVLNWAAQIYPGIKTKHLCRLIRGKMTLTEEVQWTEMAEAEYEENKIILSQEQEGCYYQESKPLEATVIKSQDNQWSYKIHQEDKILKVGKFAKIKNTHTNGVRLLAHVIQKIGKEAIVIWGQVPKFHLPVEKDVWEQWWTDYWQVTWIPEWDFISTPPLVRLVFNLVKDPIEGEETYYVDGSCSKQSKEGKAGYITDRGKDKVKVLEQTTNQQAELEAFLMALTDSGPKANIIVDSQYVMGIITGCPTESESRLVNQIIEEMIKKTEIYVAWVPAHKGIGGNQEIDHLVSQGIRQVLFLEKIEPAQEEHSKYHSNIKELVFKFGLPRLVAKQIVDTCDKCHQKGEAIHGQVNSDLGTWQMDCTHLEGKIVIVAVHVASGFIEAEVIPQETGRQTALFLLKLASRWPITHLHTDNGANFASQEVKMVAWWAGIEHTFGVPYNPQSQGVVEAMNHHLKNQIDRIREQANSVETIVLMAVHCMNFKRRGGIGDMTPAERLINMITTEQEIQFQQSKNSKFKNFRVYYREGRDQLWKGPGELLWKGEGAVILKVGTDIKVVPRRKAKIIKDYGGGKEMDSSSHMEDTGEAREVA", "length": "1448"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "86", "region_end": "93"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "2", "region_end": "3"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "10", "region_end": "15"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "18", "region_end": "24"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "32", "region_end": "33"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "43", "region_end": "47"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "54", "region_end": "66"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "69", "region_end": "78"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "84", "region_end": "85"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "96", "region_end": "98"}, {"region_type": "pfam", "region_id": "PF00077", "region_name": "Retroviral aspartyl protease", "region_start": "503", "region_end": "594"}]}}]}, "evidence": {"evidence_level": "Direct evidence", "evidence_coverage": "The full structure participates in mutual synergistic folding.", "sequence_domain": "Retroviral aspartyl protease", "complex_evidence": "Retroviral aspartyl proteases follow a two-state unfolding behavior in which folded dimers were in equilibrium with unfolded monomers. This model conforms to cases in which protein unfolding and dimer dissociation are cooperative processes in which folded monomers do not exist (PMID:1390732).", "chain_evidence": [{"chain_id": "A", "support": "N/A"}, {"chain_id": "B", "support": "N/A"}]}, "related_structures": {"id": ["MF7000986", "MF7000987"]}}}