{"entry": {"accession": "MF7000987", "general": {"name": "HIV-1 proteasw with macrocyclic peptidomimetic inhibitor 3", "pdb_id": "1z1h", "exp_method": "X-ray", "resolution": "1.85", "assembly": "Homodimer", "source_organism": "Human immunodeficiency virus type 1 group M subtype B", "publication": {"pmid": "10387041", "authors": "Martin JL, Begun J, Schindeler A, Wickramasinghe WA, Alewood D, Alewood PF, Bergman DA, Brinkworth RI, Abbenante G, March DR, Reid RC, Fairlie DP", "title": "Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease.", "journal": "Biochemistry", "year": "1999", "issue": "25", "volume": "38", "pages": "7978-88", "abstract": "High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15-17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a beta-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine-aspartate interaction induces a 1.5 A N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba67,95]HIVPR and [Lys7,Ile33,Aba67,95]HIVPR used in this work were shown to have very similar crystal structures."}}, "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:0008289", "name": "lipid binding"}, {"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:0042025", "name": "host cell nucleus"}, {"accession": "GO:0020002", "name": "host cell plasma membrane"}, {"accession": "GO:0072494", "name": "host multivesicular body"}, {"accession": "GO:0016020", "name": "membrane"}, {"accession": "GO:0019013", "name": "viral nucleocapsid"}, {"accession": "GO:0055036", "name": "virion membrane"}]}, "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:0052151", "name": "symbiont-mediated activation of host apoptosis"}, {"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": "Human immunodeficiency virus type 1 group M subtype B", "uniprot": {"id": "P03369", "start": "491", "end": "589", "coverage": "6%", "sequence": "MGARASVLSGGELDKWEKIRLRPGGKKKYKLKHIVWASRELERFAVNPGLLETSEGCRQILGQLQPSLQTGSEELRSLYNTVATLYCVHQRIDVKDTKEALEKIEEEQNKSKKKAQQAAAAAGTGNSSQVSQNYPIVQNLQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFRDYVDRFYKTLRAEQASQDVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVLAEAMSQVTNPANIMMQRGNFRNQRKTVKCFNCGKEGHIAKNCRAPRKKGCWRCGREGHQMKDCTERQANFLREDLAFLQGKAREFSSEQTRANSPTRRELQVWGGENNSLSEAGADRQGTVSFNFPQITLWQRPLVTIRIGGQLKEALLDTGADDTVLEEMNLPGKWKPKMIGGIGGFIKVRQYDQIPVEICGHKAIGTVLVGPTPVNIIGRNLLTQIGCTLNFPISPIETVPVKLKPGMDGPKVKQWPLTEEKIKALVEICTEMEKEGKISKIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLDKDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQYMDDLYVGSDLEIGQHRTKIEELRQHLLRWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQPIMLPEKDSWTVNDIQKLVGKLNWASQIYAGIKVKQLCKLLRGTKALTEVIPLTEEAELELAENREILKEPVHEVYYDPSKDLVAEIQKQGQGQWTYQIYQEPFKNLKTGKYARMRGAHTNDVKQLTEAVQKVSTESIVIWGKIPKFKLPIQKETWEAWWMEYWQATWIPEWEFVNTPPLVKLWYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTDRGRQKVVSIADTTNQKTELQAIHLALQDSGLEVNIVTDSQYALGIIQAQPDKSESELVSQIIEQLIKKEKVYLAWVPAHKGIGGNEQVDKLVSAGIRKVLFLNGIDKAQEEHEKYHSNWRAMASDFNLPPVVAKEIVASCDKCQLKGEAMHGQVDCSPGIWQLDCTHLEGKIILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTIHTDNGSNFTSTTVKAACWWAGIKQEFGIPYNPQSQGVVESMNNELKKIIGQVRDQAEHLKTAVQMAVFIHNFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQNFRVYYRDNKDPLWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQDED", "length": "1437"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "86", "region_end": "91"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "2", "region_end": "4"}, {"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": "49"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "52", "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": "496", "region_end": "587"}]}}, {"id": "B", "name": "Gag-Pol polyprotein", "source_organism": "Human immunodeficiency virus type 1 group M subtype B", "uniprot": {"id": "P03369", "start": "491", "end": "589", "coverage": "6%", "sequence": "MGARASVLSGGELDKWEKIRLRPGGKKKYKLKHIVWASRELERFAVNPGLLETSEGCRQILGQLQPSLQTGSEELRSLYNTVATLYCVHQRIDVKDTKEALEKIEEEQNKSKKKAQQAAAAAGTGNSSQVSQNYPIVQNLQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFRDYVDRFYKTLRAEQASQDVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVLAEAMSQVTNPANIMMQRGNFRNQRKTVKCFNCGKEGHIAKNCRAPRKKGCWRCGREGHQMKDCTERQANFLREDLAFLQGKAREFSSEQTRANSPTRRELQVWGGENNSLSEAGADRQGTVSFNFPQITLWQRPLVTIRIGGQLKEALLDTGADDTVLEEMNLPGKWKPKMIGGIGGFIKVRQYDQIPVEICGHKAIGTVLVGPTPVNIIGRNLLTQIGCTLNFPISPIETVPVKLKPGMDGPKVKQWPLTEEKIKALVEICTEMEKEGKISKIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLDKDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQYMDDLYVGSDLEIGQHRTKIEELRQHLLRWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQPIMLPEKDSWTVNDIQKLVGKLNWASQIYAGIKVKQLCKLLRGTKALTEVIPLTEEAELELAENREILKEPVHEVYYDPSKDLVAEIQKQGQGQWTYQIYQEPFKNLKTGKYARMRGAHTNDVKQLTEAVQKVSTESIVIWGKIPKFKLPIQKETWEAWWMEYWQATWIPEWEFVNTPPLVKLWYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTDRGRQKVVSIADTTNQKTELQAIHLALQDSGLEVNIVTDSQYALGIIQAQPDKSESELVSQIIEQLIKKEKVYLAWVPAHKGIGGNEQVDKLVSAGIRKVLFLNGIDKAQEEHEKYHSNWRAMASDFNLPPVVAKEIVASCDKCQLKGEAMHGQVDCSPGIWQLDCTHLEGKIILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTIHTDNGSNFTSTTVKAACWWAGIKQEFGIPYNPQSQGVVESMNNELKKIIGQVRDQAEHLKTAVQMAVFIHNFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQNFRVYYRDNKDPLWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQDED", "length": "1437"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "86", "region_end": "91"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "92", "region_end": "94"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "2", "region_end": "4"}, {"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": "34"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "43", "region_end": "49"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "52", "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": "496", "region_end": "587"}]}}]}, "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"]}}}