Molecule Information

General Information of the Molecule (ID: Mol04392)

• Name: OTU domain-containing protein 4 (OTUD4) ,Homo sapiens
• Synonyms: HIV-1-induced protein HIN-1
• Molecule Type: Protein
• Gene Name: OTUD4
• Gene ID: 54726
• Sequence:
  MEAAVGVPDGGDQGGAGPREDATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQSR
  HVEVRMACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFII
  Y REPNVSPSQVTENNFPEKVLLCFSNGNHYDIVYPIKYKESSAMCQSLLYELLYEKVFK
  TD VSKIVMELDTLEVADEDNSEISDSEDDSCKSKTAAAAADVNGFKPLSGNEQLKNNGN
  STS LPLSRKVLKSLNPAVYRNVEYEIWLKSKQAQQKRDYSIAAGLQYEVGDKCQVRLDH
  NGKF LNADVQGIHSENGPVLVEELGKKHTSKNLKAPPPESWNTVSGKKMKKPSTSGQNF
  HSDVD YRGPKNPSKPIKAPSALPPRLQHPSGVRQHAFSSHSSGSQSQKFSSEHKNLSRT
  PSQIIR KPDRERVEDFDHTSRESNYFGLSPEERREKQAIEESRLLYEIQNRDEQAFPAL
  SSSSVNQ SASQSSNPCVQRKSSHVGDRKGSRRRMDTEERKDKDSIHGHSQLDKRPEPST
  LENITDDK YATVSSPSKSKKLECPSPAEQKPAEHVSLSNPAPLLVSPEVHLTPAVPSLP
  ATVPAWPSE PTTFGPTGVPAPIPVLSVTQTLTTGPDSAVSQAHLTPSPVPVSIQAVNQP
  LMPLPQTLSL YQDPLYPGFPCNEKGDRAIVPPYSLCQTGEDLPKDKNILRFFFNLGVKA
  YSCPMWAPHSY LYPLHQAYLAACRMYPKVPVPVYPHNPWFQEAPAAQNESDCTCTDAHF
  PMQTEASVNGQM PQPEIGPPTFSSPLVIPPSQVSESHGQLSYQADLESETPGQLLHADY
  EESLSGKNMFPQP SFGPNPFLGPVPIAPPFFPHVWYGYPFQGFIENPVMRQNIVLPSDE
  KGELDLSLENLDLS KDCGSVSTVDEFPEARGEHVHSLPEASVSSKPDEGRTEQSSQTRK
  ADTALASIPPVAEGK AHPPTQILNRERETVPVELEPKRTIQSLKEKTEKVKDPKTAADV
  VSPGANSVDSRVQRPK EESSEDENEVSNILRSGRSKQFYNQTYGSRKYKSDWGYSGRGG
  YQHVRSEESWKGQPSRS RDEGYQYHRNVRGRPFRGDRRRSGMGDGHRGQHT
• Function: Deubiquitinase which hydrolyzes the isopeptide bond betweenthe ubiquitin C-terminus and the lysine epsilon-amino group of thetarget protein . Maynegatively regulate inflammatory and pathogen recognition signaling ininnate immune response. Upon phosphorylation at Ser-202 and Ser-204residues, via IL-1 receptor and Toll-like receptor signaling pathway,specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapterprotein triggering down-regulation of NF-kappa-B-dependenttranscription of inflammatory mediators .Independently of the catalytic activity, acts as a scaffold foralternative deubiquitinases to assemble specific deubiquitinase-substrate complexes. Associates with USP7 and USP9X deubiquitinases tostabilize alkylation repair enzyme ALKBH3, thereby promoting the repairof alkylated DNA lesions .{ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:25944111,ECO:0000269|PubMed:29395066}.
• Uniprot ID: OTUD4_HUMAN
• Ensembl ID: ENSG0000016416417
• HGNC ID: HGNC:24949

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Amprenavir

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: acquired immunodeficiency syndrome [ICD-11: 1C62.3Z] [1]

• Resistant Disease: acquired immunodeficiency syndrome [ICD-11: 1C62.3Z]
• Resistant Drug: Amprenavir
• Molecule Alteration: Mutation; Interaction
• Mechanism Description: Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV.

Disease Class: acquired immunodeficiency syndrome [ICD-11: 1C62.3Z] [1]

• Resistant Disease: acquired immunodeficiency syndrome [ICD-11: 1C62.3Z]
• Resistant Drug: Amprenavir
• Molecule Alteration: Mutation; K103N + V106M
• Mechanism Description: Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV.

Disease Class: acquired immunodeficiency syndrome [ICD-11: 1C62.3Z] [1]

• Resistant Disease: acquired immunodeficiency syndrome [ICD-11: 1C62.3Z]
• Resistant Drug: Amprenavir
• Molecule Alteration: Mutation; K114N
• Mechanism Description: Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV.

References

• Ref 1: Decoding drug resistant mechanism of V32I, I50V and I84V mutations of HIV-1 protease on amprenavir binding by using molecular dynamics simulations and MM-GBSA calculations. SAR QSAR Environ Res. 2022 Oct;33(10):805-831.