5uno

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Crystal Structure of Hip1 (Rv2224c)

Structural highlights

5uno is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.603Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HIP1_MYCTU Serine protease that promotes tuberculosis (TB) pathogenesis by promoting the processing and the extracellular release of the M.tuberculosis (Mtb) heat-shock protein GroEL2 (PubMed:18172199, PubMed:24830429, PubMed:28346784). Hip1-dependent cleavage of multimeric GroEL2 results in release of cleaved monomeric GroEL2 into the extracellular milieu. Conversion of multimeric GroEL2 into monomeric GroEL2 is likely to be a mechanism for regulating GroEL2 functions during Mtb pathogenesis (PubMed:24830429). In vitro, exhibits proteolytic activity against synthetic peptides and the general protease substrate azocasein, and exhibits esterase activity against the ester substrate p-nitrophenylbutyrate (PubMed:24830429, PubMed:28346784).[1] [2] [3] Key immunomodulatory virulence factor, which promotes survival in host macrophages and modulates host immune responses (PubMed:18172199, PubMed:21947769, PubMed:24659689). Impacts host innate immune responses by preventing robust macrophage activation (PubMed:18172199, PubMed:21947769). Dampens macrophage pro-inflammatory responses by limiting toll-like receptor 2 (TLR2) activation. It also dampens TLR2-independent activation of the inflammasome and limits secretion of interleukin-18 (IL-18). May act by masking cell surface interactions between TLR2 agonists on Mtb and TLR2 on macrophages (PubMed:21947769). In addition, impacts host adaptive immune responses. It prevents robust maturation of infected dendritic cells (DCs), limits the secretion of key pro-inflammatory cytokines such as IL-12, impairs Ag presentation, and modulates the nature of Ag-specific T-cell responses (PubMed:24659689).[4] [5] [6]

Publication Abstract from PubMed

The Mycobacterium tuberculosis (Mtb) serine protease Hip1 (hydrolase important for pathogenesis; Rv2224c) promotes tuberculosis (TB) pathogenesis by impairing host immune responses through proteolysis of a protein substrate, Mtb GroEL2. The cell surface localization of Hip1 and its immunomodulatory functions make Hip1 a good drug target for new adjunctive immune therapies for TB. Here, we report the crystal structure of Hip1 to a resolution of 2.6 A and the kinetic studies of the enzyme against model substrates and the protein GroEL2. The structure shows a two-domain protein, one of which contains the catalytic residues that are the signature of a serine protease. Surprisingly, a threonine is located within the active site close enough to hydrogen bond with the catalytic residues Asp463 and His490. Mutation of this residue, Thr466, to alanine established its importance for function. Our studies provide insights into the structure of a member of a novel family of proteases. Knowledge of the Hip1 structure will aid in designing inhibitors that could block Hip1 activity.

Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c).,Naffin-Olivos JL, Daab A, White A, Goldfarb NE, Milne AC, Liu D, Baikovitz J, Dunn BM, Rengarajan J, Petsko GA, Ringe D Biochemistry. 2017 Apr 7. doi: 10.1021/acs.biochem.6b01066. PMID:28346784[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
1 reviews cite this structure
Chemical approaches to unraveling the biology of mycobacteria.
Finin et al. (2023)
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4 other articles
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See Also

References

  1. ↑ Rengarajan J, Murphy E, Park A, Krone CL, Hett EC, Bloom BR, Glimcher LH, Rubin EJ. Mycobacterium tuberculosis Rv2224c modulates innate immune responses. Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):264-9. PMID:18172199 doi:10.1073/pnas.0710601105
  2. ↑ Naffin-Olivos JL, Georgieva M, Goldfarb N, Madan-Lala R, Dong L, Bizzell E, Valinetz E, Brandt GS, Yu S, Shabashvili DE, Ringe D, Dunn BM, Petsko GA, Rengarajan J. Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. PLoS Pathog. 2014 May 15;10(5):e1004132. PMID:24830429 doi:10.1371/journal.ppat.1004132
  3. ↑ Naffin-Olivos JL, Daab A, White A, Goldfarb NE, Milne AC, Liu D, Baikovitz J, Dunn BM, Rengarajan J, Petsko GA, Ringe D. Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c). Biochemistry. 2017 Apr 7. doi: 10.1021/acs.biochem.6b01066. PMID:28346784 doi:http://dx.doi.org/10.1021/acs.biochem.6b01066
  4. ↑ Rengarajan J, Murphy E, Park A, Krone CL, Hett EC, Bloom BR, Glimcher LH, Rubin EJ. Mycobacterium tuberculosis Rv2224c modulates innate immune responses. Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):264-9. PMID:18172199 doi:10.1073/pnas.0710601105
  5. ↑ Madan-Lala R, Peixoto KV, Re F, Rengarajan J. Mycobacterium tuberculosis Hip1 dampens macrophage proinflammatory responses by limiting toll-like receptor 2 activation. Infect Immun. 2011 Dec;79(12):4828-38. PMID:21947769 doi:10.1128/IAI.05574-11
  6. ↑ Madan-Lala R, Sia JK, King R, Adekambi T, Monin L, Khader SA, Pulendran B, Rengarajan J. Mycobacterium tuberculosis impairs dendritic cell functions through the serine hydrolase Hip1. J Immunol. 2014 May 1;192(9):4263-72. PMID:24659689 doi:10.4049/jimmunol.1303185
  7. ↑ Naffin-Olivos JL, Daab A, White A, Goldfarb NE, Milne AC, Liu D, Baikovitz J, Dunn BM, Rengarajan J, Petsko GA, Ringe D. Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c). Biochemistry. 2017 Apr 7. doi: 10.1021/acs.biochem.6b01066. PMID:28346784 doi:http://dx.doi.org/10.1021/acs.biochem.6b01066

Contents


PDB ID 5uno

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