I agree. The Fourth Crusade was an utter disaster for the Byzantines.1453
In all seriousness? Probably the Fourth Crusade, 1204.
It permanently crippled the Romans and delivered a mortal blow that they never truly recovered from.
Think there's two distinct but related questions going on here
When was ERE unable to save themselves.
When was ERE unable to be saved by foreign forces, either directly or indirectly helping.
As for the first one, Common opinion would probably to succed defending against the Forth Crusade in 1204 (or thereabout depending on when ERE would have to start changing to be ready for it, given butterfly-nets keeping it arriving on date), The later on is much tougher to guesstimate
The Ottoman interregnum was a really good opportunity.
Of which they had no capability of taking advantage of. Which is a big problem for any post 1204 timeline, they're flat broke with no real ability to take advantage of opportunities in front of them.
Eh, I wouldn't say that until 1347.