4HW4

Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design

External Resource: Annotation

Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations
Protein Modification Annotation

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
A	SCOP2B Superfamily	Bcl-2-like inhibitors of programmed cell death	8083810	3001974	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	Bcl-2-like inhibitors of programmed cell death	8083810	3001974	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	Bcl-2	e4hw4A1	A: alpha arrays	X: Toxins' membrane translocation domains	H: Bcl-2 inhibitors of programmed cell death (From Topology)	T: Bcl-2 inhibitors of programmed cell death	F: Bcl-2	ECOD (1.6)
B	Bcl-2	e4hw4B1	A: alpha arrays	X: Toxins' membrane translocation domains	H: Bcl-2 inhibitors of programmed cell death (From Topology)	T: Bcl-2 inhibitors of programmed cell death	F: Bcl-2	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	1.10.437.10	Mainly Alpha	Orthogonal Bundle	Apoptosis Regulator Bcl-x	Blc2-like	CATH (4.3.0)
B	1.10.437.10	Mainly Alpha	Orthogonal Bundle	Apoptosis Regulator Bcl-x	Blc2-like	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B	PF00452	Apoptosis regulator proteins, Bcl-2 family (Bcl-2)	Apoptosis regulator proteins, Bcl-2 family	-	Family

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B	Induced myeloid leukemia cell differentiation protein Mcl-1	macromolecule transmembrane transporter activity protein transporter activity protein transmembrane transporter activity transporter activity transmembrane transporter activity protein heterodimerization activity protein binding binding protein dimerization activity BH domain binding protein domain specific binding death domain binding BH3 domain binding passive transmembrane transporter activity macromolecule transmembrane transporter activity protein transporter activity protein transmembrane transporter activity transporter activity transmembrane transporter activity protein heterodimerization activity protein binding binding protein dimerization activity BH domain binding protein domain specific binding death domain binding BH3 domain binding passive transmembrane transporter activity channel activity	cellular response to stimulus cellular response to stress response to stimulus DNA damage response response to stress cellular process positive regulation of cell communication intrinsic apoptotic signaling pathway in response to oxidative stress neuron apoptotic process regulation of cellular process positive regulation of signal transduction regulation of oxidative stress-induced intrinsic apoptotic signaling pathway signaling positive regulation of biological process cellular response to stimulus cellular response to stress response to stimulus DNA damage response response to stress cellular process positive regulation of cell communication intrinsic apoptotic signaling pathway in response to oxidative stress neuron apoptotic process regulation of cellular process positive regulation of signal transduction regulation of oxidative stress-induced intrinsic apoptotic signaling pathway signaling positive regulation of biological process regulation of signal transduction regulation of programmed cell death regulation of intrinsic apoptotic signaling pathway positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway intracellular signal transduction cell communication positive regulation of apoptotic signaling pathway positive regulation of response to stimulus regulation of intracellular signal transduction signal transduction intrinsic apoptotic signaling pathway positive regulation of neuron apoptotic process positive regulation of cellular process regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway regulation of biological process regulation of signaling positive regulation of programmed cell death regulation of apoptotic process biological regulation positive regulation of intracellular signal transduction cell death positive regulation of apoptotic process neuron intrinsic apoptotic signaling pathway in response to oxidative stress apoptotic signaling pathway regulation of response to stimulus positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway regulation of cell communication positive regulation of intrinsic apoptotic signaling pathway apoptotic process programmed cell death regulation of neuron apoptotic process regulation of apoptotic signaling pathway positive regulation of signaling cellular homeostasis homeostatic process negative regulation of extrinsic apoptotic signaling pathway in absence of ligand signal transduction in absence of ligand negative regulation of signaling negative regulation of biological process negative regulation of cell communication extrinsic apoptotic signaling pathway negative regulation of signal transduction in absence of ligand negative regulation of extrinsic apoptotic signaling pathway negative regulation of apoptotic signaling pathway negative regulation of cellular process extrinsic apoptotic signaling pathway in absence of ligand cell surface receptor signaling pathway negative regulation of response to stimulus negative regulation of programmed cell death negative regulation of signal transduction regulation of extrinsic apoptotic signaling pathway negative regulation of apoptotic process regulation of extrinsic apoptotic signaling pathway in absence of ligand organelle fusion cellular component organization organelle organization mitochondrial fusion cellular component organization or biogenesis mitochondrion organization regulation of anoikis negative regulation of anoikis anoikis response to peptide response to chemical response to cytokine developmental process cellular developmental process cell differentiation cell fate determination cell fate commitment intrinsic apoptotic signaling pathway in response to DNA damage negative regulation of catabolic process catabolic process negative regulation of metabolic process autophagy regulation of catabolic process regulation of autophagy negative regulation of autophagy metabolic process process utilizing autophagic mechanism regulation of metabolic process apoptotic mitochondrial changes release of cytochrome c from mitochondria	membrane-bounded organelle intracellular organelle cellular anatomical structure intracellular anatomical structure mitochondrion organelle cytoplasm intracellular membrane-bounded organelle membrane cytosol protein-containing complex Bcl-2 family protein complex nucleus membrane-enclosed lumen membrane-bounded organelle intracellular organelle cellular anatomical structure intracellular anatomical structure mitochondrion organelle cytoplasm intracellular membrane-bounded organelle membrane cytosol protein-containing complex Bcl-2 family protein complex nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen nuclear lumen mitochondrial membrane organelle outer membrane organelle envelope bounding membrane of organelle mitochondrial envelope mitochondrial outer membrane outer membrane organelle membrane
C, D	Mcl-1 BH3 peptide	-	-	-

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B	IPR020726	Apoptosis regulator, Bcl-2, BH2 motif, conserved site	Conserved Site
A, B	IPR036834	Bcl-2-like superfamily	Homologous Superfamily
A, B	IPR046371	Bcl-2, Bcl-2 homology region 1-3	Domain
A, B	IPR002475	Bcl2-like	Family
A, B	IPR026298	Bcl-2 family	Family
A, B	IPR020717	Apoptosis regulator, Bcl-2, BH1 motif, conserved site	Conserved Site
A, B	IPR013281	Apoptosis regulator, Mcl-1	Family
A, B	IPR020728	Apoptosis regulator, Bcl-2, BH3 motif, conserved site	Conserved Site

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B	Pharos: Q07820	Barrett esophagus plasma cell myeloma leishmaniasis spindle cell sarcoma primary cutaneous T-cell non-Hodgkin lymphoma sarcoma subependymal giant cell astrocytoma interstitial lung disease lung carcinoma Lymphoma, T-Cell, Cutaneous adenoma myeloid neoplasm cancer osteosarcoma Pick disease Barrett esophagus plasma cell myeloma leishmaniasis spindle cell sarcoma primary cutaneous T-cell non-Hodgkin lymphoma sarcoma subependymal giant cell astrocytoma interstitial lung disease lung carcinoma Lymphoma, T-Cell, Cutaneous adenoma myeloid neoplasm cancer osteosarcoma Pick disease diabetes mellitus plasma cell neoplasm gastric cancer primitive neuroectodermal tumor glioblastoma sinusitis hereditary spastic paraplegia ulcerative colitis invasive ductal breast carcinoma lung benign neoplasm malignant ependymoma astrocytic tumor malignant pancreatic neoplasm non-small cell lung carcinoma ovarian cancer chronic obstructive pulmonary disease pilocytic astrocytoma Down syndrome polycystic ovary syndrome gastric carcinoma psoriasis granulomatous slack skin disease interstitial cystitis large cell medulloblastoma lung cancer lymphatic system disease malignant glioma atypical teratoid rhabdoid tumor medulloblastoma breast carcinoma osteoarthritis pancreatic ductal adenocarcinoma cutaneous lupus erythematosus epithelioid sarcoma Gaucher disease hematologic disease

Protein Modification Annotation

Modified Residue(s)
Chain	Residue(s)	Description
C, D	ACE	RESID: AA0041 , AA0042 , AA0043 , AA0044 , AA0045 , AA0046 , AA0049 , AA0050 , AA0051 , AA0052 , AA0053 , AA0054 , AA0354 PSI-MOD : N-acetyl-L-alanine MOD:00050 , N-acetyl-L-aspartic acid MOD:00051 , N-acetyl-L-cysteine MOD:00052 , N-acetyl-S-archeol-cysteine MOD:00897 , N-acetyl-L-glutamic acid MOD:00053 , N-acetyl-L-glutamine MOD:00054 , N-acetylglycine MOD:00055 , N-acetyl-L-methionine MOD:00058 , N-acetyl-L-proline MOD:00059 , N-acetyl-L-serine MOD:00060 , N,O-diacetylated L-serine MOD:00648 , N-acetyl-L-threonine MOD:00061 , N-acetyl-L-tyrosine MOD:00062 , N-acetyl-L-valine MOD:00063 , N2-acetyl-L-arginine MOD:00359
C, D	NH2	RESID: AA0041 , AA0042 , AA0043 , AA0044 , AA0045 , AA0046 , AA0049 , AA0050 , AA0051 , AA0052 , AA0053 , AA0054 , AA0354 , AA0081 , AA0083 , AA0084 , AA0086 , AA0087 , AA0088 , AA0090 , AA0091 , AA0092 , AA0093 , AA0095 , AA0096 , AA0097 , AA0098 , AA0099 , AA0100 PSI-MOD : N-acetyl-L-alanine MOD:00050 , N-acetyl-L-aspartic acid MOD:00051 , N-acetyl-L-cysteine MOD:00052 , N-acetyl-S-archeol-cysteine MOD:00897 , N-acetyl-L-glutamic acid MOD:00053 , N-acetyl-L-glutamine MOD:00054 , N-acetylglycine MOD:00055 , N-acetyl-L-methionine MOD:00058 , N-acetyl-L-proline MOD:00059 , N-acetyl-L-serine MOD:00060 , N,O-diacetylated L-serine MOD:00648 , N-acetyl-L-threonine MOD:00061 , N-acetyl-L-tyrosine MOD:00062 , N-acetyl-L-valine MOD:00063 , N2-acetyl-L-arginine MOD:00359 , L-alanine amide MOD:00090 , L-asparagine amide MOD:00092 , L-aspartic acid 1-amide MOD:00093 , L-glutamine amide MOD:00095 , L-glutamic acid 1-amide MOD:00096 , glycine amide MOD:00097 , L-isoleucine amide MOD:00099 , L-leucine amide MOD:00100 , L-lysine amide MOD:00101 , L-methionine amide MOD:00102 , L-proline amide MOD:00104 , L-serine amide MOD:00105 , L-threonine amide MOD:00106 , L-tryptophan amide MOD:00107 , L-tyrosine amide MOD:00108 , L-valine amide MOD:00109

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.