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5yr6

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Human methionine aminopeptidase type 1b (F309L mutant) in complex with TNP470

Structural highlights

5yr6 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.75Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MAP11_HUMAN Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Required for normal progression through the cell cycle.[HAMAP-Rule:MF_03174]^[1] ^[2]

Publication Abstract from PubMed

Natural product ovalicin and its synthetic derivative TNP-470 have been extensively studied for their anti-angiogenic property, and the later reached phase 3 clinical trials. They covalently modify the conserved histidine in Type 2 methionine aminopeptidases (MetAPs) at nanomolar concentrations. Even though a similar mechanism is possible in Type 1 human MetAP, it is inhibited only at millimolar concentration. In this study, we have discovered two Type 1 wild type MetAPs ( S. pneumoniae and E. faecalis ) that are inhibited at low micromolar to nanomolar concentrations, and established the molecular mechanism. F309 in the active site of human Type 1 MetAP ( Hs MetAP1b) seems to be the key to the resistance, while newly identified ovalicin sensitive Type 1 MetAPs have a methionine or isoleucine at this position. Type 2 human MetAP ( Hs MetAP2) also has an isoleucine (I338) in the analogous position. Ovalicin inhibited F309M and F309I mutants of human MetAP1b at low micromolar concentration. MD simulations suggest that ovalicin is not stably placed in the active site of wild type MetAP1b before the covalent modification. In the case of F309M mutant and human Type 2 MetAP, molecule spends more time in the active site providing time for covalent modification.

Discovery of Natural Product Ovalicin Sensitive Type 1 Methionine Aminopeptidases: Molecular and Structural Basis.,Pillalamarri V, Arya T, Haque N, Bala SC, Marapaka AK, Addlagatta A Biochem J. 2019 Mar 5. pii: BCJ20180874. doi: 10.1042/BCJ20180874. PMID:30837307^[3]

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

References

↑ Addlagatta A, Hu X, Liu JO, Matthews BW. Structural basis for the functional differences between type I and type II human methionine aminopeptidases. Biochemistry. 2005 Nov 15;44(45):14741-9. PMID:16274222 doi:10.1021/bi051691k
↑ Hu X, Addlagatta A, Lu J, Matthews BW, Liu JO. Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18148-53. Epub 2006 Nov 17. PMID:17114291
↑ Pillalamarri V, Arya T, Haque N, Bala SC, Marapaka AK, Addlagatta A. Discovery of Natural Product Ovalicin Sensitive Type 1 Methionine Aminopeptidases: Molecular and Structural Basis. Biochem J. 2019 Mar 5. pii: BCJ20180874. doi: 10.1042/BCJ20180874. PMID:30837307 doi:http://dx.doi.org/10.1042/BCJ20180874